@article {1016, title = {Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 04 05}, abstract = {

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10\% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

}, keywords = {Adolescent, Adult, Aged, Antibodies, Neutralizing, Autoantibodies, Autoimmune Diseases, COVID-19, Female, Genetic Diseases, Inborn, HEK293 Cells, Humans, Interferon-alpha, Male, Middle Aged, Receptor, Interferon alpha-beta, SARS-CoV-2, Vaccines, Attenuated, Yellow Fever Vaccine, Yellow fever virus}, issn = {1540-9538}, doi = {10.1084/jem.20202486}, author = {Bastard, Paul and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Chbihi, Marwa and Le Voyer, Tom and Rosain, J{\'e}r{\'e}mie and Philippot, Quentin and Seeleuthner, Yoann and Gervais, Adrian and Materna, Marie and de Oliveira, Patricia Mouta Nunes and Maia, Maria de Lourdes S and Dinis Ano Bom, Ana Paula and Azamor, Tamiris and Ara{\'u}jo da Concei{\c c}{\~a}o, Deborah and Goudouris, Ekaterini and Homma, Akira and Slesak, G{\"u}nther and Sch{\"a}fer, Johannes and Pulendran, Bali and Miller, Joseph D and Huits, Ralph and Yang, Rui and Rosen, Lindsey B and Bizien, Lucy and Lorenzo, Lazaro and Chrabieh, Maya and Erazo, Lucia V and Rozenberg, Flore and Jeljeli, Mohamed Maxime and B{\'e}ziat, Vivien and Holland, Steven M and Cobat, Aurelie and Notarangelo, Luigi D and Su, Helen C and Ahmed, Rafi and Puel, Anne and Zhang, Shen-Ying and Abel, Laurent and Seligman, Stephen J and Zhang, Qian and MacDonald, Margaret R and Jouanguy, Emmanuelle and Rice, Charles M and Casanova, Jean-Laurent} } @article {894, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {1002, title = {Plasma Exchange to Rescue Patients with Autoantibodies Against Type I Interferons and Life-Threatening COVID-19 Pneumonia.}, journal = {J Clin Immunol}, volume = {41}, year = {2021}, month = {2021 04}, pages = {536-544}, abstract = {

PURPOSE: To report four cases of life-threatening COVID-19 pneumonia in patients with high blood concentrations of neutralizing autoantibodies against type I interferons (IFNs), who were treated with plasma exchange (PE) as a rescue therapy.

METHODS: Prospective case series, which included patients, diagnosed with RT-PCR-confirmed SARS-CoV-2 infection and positive autoantibodies against type I IFNs in two French intensive care units (ICUs) between October 8 and November 14, 2020. Six critically ill COVID-19 patients with no anti-IFN antibodies were used as controls. Anti-IFN autoantibodies and IFN concentrations, together with the levels of anti-SARS-CoV-2 antibodies, were measured sequentially in serum. Viral load was determined in the upper and lower respiratory tract. Patients were followed during hospital stay.

RESULTS: Three men and one woman were included. Three of the patients had four PE sessions each, while another had three PE sessions. PE decreased the concentrations of autoantibodies against type I IFN in all four patients, whereas anti-SARS-CoV-2 antibody levels remained stable. Autoantibodies against type I IFN levels were high in tracheal aspirates of one patient and decreased after three PE sessions. By contrast, anti-IFN autoantibodies were not detected in tracheal aspirates from five control patients without detectable anti-IFN autoantibodies in serum. During PE, serum IFN-α levels slightly increased in three out of four patients, and upper respiratory tract viral load decreased in all patients. All patients were alive at day 28 of ICU admission. Two patients eventually died in the ICU, while the two survivors were discharged from the ICU at days 50 and 66.

CONCLUSIONS: PE efficiently removes autoantibodies against type I IFNs, including those detected in tracheal aspirates, without affecting anti-SARS-CoV-2 antibody levels, in patients with life-threatening COVID-19 pneumonia. The clinical benefit of PE in patients with autoantibodies against type I IFNs should be tested in a larger study.

}, keywords = {Adult, Aged, Autoantibodies, COVID-19, Female, Humans, Interferon Type I, Male, Plasma Exchange, Prospective Studies, SARS-CoV-2}, issn = {1573-2592}, doi = {10.1007/s10875-021-00994-9}, author = {de Prost, Nicolas and Bastard, Paul and Arrestier, Romain and Fourati, Slim and Mah{\'e}vas, Mathieu and Burrel, Sonia and Dorgham, Karim and Gorochov, Guy and Tandjaoui-Lambiotte, Yacine and Azzaoui, Iname and Fernandes, Ignacio and Combes, Alain and Casanova, Jean-Laurent and Mekontso-Dessap, Armand and Luyt, Charles-Edouard} } @article {897, title = {Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {431-445}, abstract = {

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

}, keywords = {African Americans, Aged, Aged, 80 and over, Calbindin 2, Colitis, Ulcerative, Crohn Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP4 Subtype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.001}, author = {Somineni, Hari K and Nagpal, Sini and Venkateswaran, Suresh and Cutler, David J and Okou, David T and Haritunians, Talin and Simpson, Claire L and Begum, Ferdouse and Datta, Lisa W and Quiros, Antonio J and Seminerio, Jenifer and Mengesha, Emebet and Alexander, Jonathan S and Baldassano, Robert N and Dudley-Brown, Sharon and Cross, Raymond K and Dassopoulos, Themistocles and Denson, Lee A and Dhere, Tanvi A and Iskandar, Heba and Dryden, Gerald W and Hou, Jason K and Hussain, Sunny Z and Hyams, Jeffrey S and Isaacs, Kim L and Kader, Howard and Kappelman, Michael D and Katz, Jeffry and Kellermayer, Richard and Kuemmerle, John F and Lazarev, Mark and Li, Ellen and Mannon, Peter and Moulton, Dedrick E and Newberry, Rodney D and Patel, Ashish S and Pekow, Joel and Saeed, Shehzad A and Valentine, John F and Wang, Ming-Hsi and McCauley, Jacob L and Abreu, Maria T and Jester, Traci and Molle-Rios, Zarela and Palle, Sirish and Scherl, Ellen J and Kwon, John and Rioux, John D and Duerr, Richard H and Silverberg, Mark S and Zwick, Michael E and Stevens, Christine and Daly, Mark J and Cho, Judy H and Gibson, Greg and McGovern, Dermot P B and Brant, Steven R and Kugathasan, Subra} } @article {950, title = {8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 03 23}, pages = {1523}, abstract = {

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9\% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

}, keywords = {Aged, Case-Control Studies, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Mutation, Prostatic Neoplasms, Protective Factors, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-15122-1}, author = {Dupont, William D and Breyer, Joan P and Plummer, W Dale and Chang, Sam S and Cookson, Michael S and Smith, Joseph A and Blue, Elizabeth E and Bamshad, Michael J and Smith, Jeffrey R} } @article {880, title = {Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 04 01}, pages = {e203959}, abstract = {

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening.

Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.

Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.

Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.

Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.

Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55\%]), 441 (0.9\%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3\%) for familial hypercholesterolemia, 235 (0.5\%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2\%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4\%) vs 4663 of 49 607 noncarriers (9.4\%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6\%) vs 2080 of 27 028 female noncarriers (7.7\%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4\%) vs 929 of 49 662 noncarriers (1.9\%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3\% for carriers of familial hypercholesterolemia, 41.1\% for hereditary breast and ovarian cancer syndrome, and 38.3\% for Lynch syndrome. Across the 3 conditions, 39.7\% (175 of 441) of the carriers reported a family history of disease vs 23.2\% (34 517 of 148 772) of noncarriers.

Conclusions and Relevance: The findings suggest that approximately 1\% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

}, keywords = {Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome, Heterozygote, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Pedigree, Proportional Hazards Models, United Kingdom, Whole Exome Sequencing}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.3959}, author = {Patel, Aniruddh P and Wang, Minxian and Fahed, Akl C and Mason-Suares, Heather and Brockman, Deanna and Pelletier, Renee and Amr, Sami and Machini, Kalotina and Hawley, Megan and Witkowski, Leora and Koch, Christopher and Philippakis, Anthony and Cassa, Christopher A and Ellinor, Patrick T and Kathiresan, Sekar and Ng, Kenney and Lebo, Matthew and Khera, Amit V} } @article {904, title = {Autoantibodies against type I IFNs in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6\% of women and 12.5\% of men.

}, keywords = {Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Asymptomatic Infections, Autoantibodies, Betacoronavirus, Case-Control Studies, Coronavirus Infections, COVID-19, Critical Illness, Female, Humans, Immunoglobulin G, Interferon alpha-2, Interferon Type I, Male, Middle Aged, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {1095-9203}, doi = {10.1126/science.abd4585}, author = {Bastard, Paul and Rosen, Lindsey B and Zhang, Qian and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Zhang, Yu and Dorgham, Karim and Philippot, Quentin and Rosain, J{\'e}r{\'e}mie and B{\'e}ziat, Vivien and Manry, Jeremy and Shaw, Elana and Haljasm{\"a}gi, Liis and Peterson, P{\"a}rt and Lorenzo, Lazaro and Bizien, Lucy and Trouillet-Assant, Sophie and Dobbs, Kerry and de Jesus, Adriana Almeida and Belot, Alexandre and Kallaste, Anne and Catherinot, Emilie and Tandjaoui-Lambiotte, Yacine and Le Pen, J{\'e}r{\'e}mie and Kerner, Gaspard and Bigio, Benedetta and Seeleuthner, Yoann and Yang, Rui and Bolze, Alexandre and Spaan, Andr{\'a}s N and Delmonte, Ottavia M and Abers, Michael S and Aiuti, Alessandro and Casari, Giorgio and Lampasona, Vito and Piemonti, Lorenzo and Ciceri, Fabio and Bilguvar, Kaya and Lifton, Richard P and Vasse, Marc and Smadja, David M and Migaud, M{\'e}lanie and Hadjadj, J{\'e}rome and Terrier, Benjamin and Duffy, Darragh and Quintana-Murci, Lluis and van de Beek, Diederik and Roussel, Lucie and Vinh, Donald C and Tangye, Stuart G and Haerynck, Filomeen and Dalmau, David and Martinez-Picado, Javier and Brodin, Petter and Nussenzweig, Michel C and Boisson-Dupuis, St{\'e}phanie and Rodr{\'\i}guez-Gallego, Carlos and Vogt, Guillaume and Mogensen, Trine H and Oler, Andrew J and Gu, Jingwen and Burbelo, Peter D and Cohen, Jeffrey I and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio, Mariella and Bonfanti, Paolo and Rossignol, Patrick and Mayaux, Julien and Rieux-Laucat, Fr{\'e}d{\'e}ric and Husebye, Eystein S and Fusco, Francesca and Ursini, Matilde Valeria and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Castagnoli, Riccardo and Montagna, Daniela and Licari, Amelia and Marseglia, Gian Luigi and Duval, Xavier and Ghosn, Jade and Tsang, John S and Goldbach-Mansky, Raphaela and Kisand, Kai and Lionakis, Michail S and Puel, Anne and Zhang, Shen-Ying and Holland, Steven M and Gorochov, Guy and Jouanguy, Emmanuelle and Rice, Charles M and Cobat, Aurelie and Notarangelo, Luigi D and Abel, Laurent and Su, Helen C and Casanova, Jean-Laurent} } @article {864, title = {Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.}, journal = {Stroke}, volume = {51}, year = {2020}, month = {2020 07}, pages = {2153-2160}, abstract = {

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the () gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and genotype predict ICH recurrence. We then developed and validated a combined -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

RESULTS: Cortical superficial siderosis, cerebral microbleed, and ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all <0.05). Combining genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6\%, 2.5\%, and 0.9\%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

CONCLUSIONS: Combining MRI and genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

}, keywords = {Aged, Anticoagulants, Apolipoprotein E4, Cerebral Hemorrhage, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Recurrence}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.120.028310}, author = {Biffi, Alessandro and Urday, Sebastian and Kubiszewski, Patryk and Gilkerson, Lee and Sekar, Padmini and Rodriguez-Torres, Axana and Bettin, Margaret and Charidimou, Andreas and Pasi, Marco and Kourkoulis, Christina and Schwab, Kristin and DiPucchio, Zora and Behymer, Tyler and Osborne, Jennifer and Morgan, Misty and Moomaw, Charles J and James, Michael L and Greenberg, Steven M and Viswanathan, Anand and Gurol, M Edip and Worrall, Bradford B and Testai, Fernando D and McCauley, Jacob L and Falcone, Guido J and Langefeld, Carl D and Anderson, Christopher D and Kamel, Hooman and Woo, Daniel and Sheth, Kevin N and Rosand, Jonathan} } @article {855, title = {Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {40}, year = {2020}, month = {2020 11}, pages = {2738-2746}, abstract = {

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malm{\"o} Diet and Cancer Study, of whom 4122 (14.4\%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16\% for those in the lowest GPS decile to 48\% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

CONCLUSIONS: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

}, keywords = {Adult, Aged, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Heredity, Humans, Incidence, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Prognosis, Risk Assessment, Sweden, Time Factors, United Kingdom}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.120.314856}, author = {Hindy, George and Aragam, Krishna G and Ng, Kenney and Chaffin, Mark and Lotta, Luca A and Baras, Aris and Drake, Isabel and Orho-Melander, Marju and Melander, Olle and Kathiresan, Sekar and Khera, Amit V} } @article {903, title = {Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5\%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, Child, Child, Preschool, Coronavirus Infections, COVID-19, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7, Interferon Type I, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral, Receptor, Interferon alpha-beta, SARS-CoV-2, Toll-Like Receptor 3, Young Adult}, issn = {1095-9203}, doi = {10.1126/science.abd4570}, author = {Zhang, Qian and Bastard, Paul and Liu, Zhiyong and Le Pen, J{\'e}r{\'e}mie and Moncada-Velez, Marcela and Chen, Jie and Ogishi, Masato and Sabli, Ira K D and Hodeib, Stephanie and Korol, Cecilia and Rosain, J{\'e}r{\'e}mie and Bilguvar, Kaya and Ye, Junqiang and Bolze, Alexandre and Bigio, Benedetta and Yang, Rui and Arias, Andr{\'e}s Augusto and Zhou, Qinhua and Zhang, Yu and Onodi, Fanny and Korniotis, Sarantis and Karpf, L{\'e}a and Philippot, Quentin and Chbihi, Marwa and Bonnet-Madin, Lucie and Dorgham, Karim and Smith, Nika{\"\i}a and Schneider, William M and Razooky, Brandon S and Hoffmann, Hans-Heinrich and Michailidis, Eleftherios and Moens, Leen and Han, Ji Eun and Lorenzo, Lazaro and Bizien, Lucy and Meade, Philip and Neehus, Anna-Lena and Ugurbil, Aileen Camille and Corneau, Aur{\'e}lien and Kerner, Gaspard and Zhang, Peng and Rapaport, Franck and Seeleuthner, Yoann and Manry, Jeremy and Masson, Cecile and Schmitt, Yohann and Schluter, Agatha and Le Voyer, Tom and Khan, Taushif and Li, Juan and Fellay, Jacques and Roussel, Lucie and Shahrooei, Mohammad and Alosaimi, Mohammed F and Mansouri, Davood and Al-Saud, Haya and Al-Mulla, Fahd and Almourfi, Feras and Al-Muhsen, Saleh Zaid and Alsohime, FAHd and Al Turki, Saeed and Hasanato, Rana and van de Beek, Diederik and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio{\textquoteright}, Mariella and Bonfanti, Paolo and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Oler, Andrew J and Tompkins, Miranda F and Alba, Camille and Vandernoot, Isabelle and Goffard, Jean-Christophe and Smits, Guillaume and Migeotte, Isabelle and Haerynck, Filomeen and Soler-Palacin, Pere and Martin-Nalda, Andrea and Colobran, Roger and Morange, Pierre-Emmanuel and Keles, Sevgi and {\c C}{\"o}lkesen, Fatma and Ozcelik, Tayfun and Yasar, Kadriye Kart and Senoglu, Sevtap and Karabela, {\c S}emsi Nur and Rodr{\'\i}guez-Gallego, Carlos and Novelli, Giuseppe and Hraiech, Sami and Tandjaoui-Lambiotte, Yacine and Duval, Xavier and Laou{\'e}nan, C{\'e}dric and Snow, Andrew L and Dalgard, Clifton L and Milner, Joshua D and Vinh, Donald C and Mogensen, Trine H and Marr, Nico and Spaan, Andr{\'a}s N and Boisson, Bertrand and Boisson-Dupuis, St{\'e}phanie and Bustamante, Jacinta and Puel, Anne and Ciancanelli, Michael J and Meyts, Isabelle and Maniatis, Tom and Soumelis, Vassili and Amara, Ali and Nussenzweig, Michel and Garc{\'\i}a-Sastre, Adolfo and Krammer, Florian and Pujol, Aurora and Duffy, Darragh and Lifton, Richard P and Zhang, Shen-Ying and Gorochov, Guy and B{\'e}ziat, Vivien and Jouanguy, Emmanuelle and Sancho-Shimizu, Vanessa and Rice, Charles M and Abel, Laurent and Notarangelo, Luigi D and Cobat, Aurelie and Su, Helen C and Casanova, Jean-Laurent} } @article {835, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, keywords = {Adult, Africa, African Continental Ancestry Group, Aged, Aged, 80 and over, alpha Karyopherins, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Gon{\c c}alo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {747, title = {Mutations in KRT10 in epidermolytic acanthoma.}, journal = {J Cutan Pathol}, volume = {47}, year = {2020}, month = {2020 Jun}, pages = {524-529}, abstract = {

BACKGROUND: Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA.

METHODS: Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis.

RESULTS: DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10.

CONCLUSIONS: Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.

}, keywords = {Acanthoma, Adult, Aged, Aged, 80 and over, Female, Genomics, Humans, Hyperkeratosis, Epidermolytic, Ichthyosis Bullosa of Siemens, Keratin-10, Keratins, Male, Middle Aged, Mutation, Skin Neoplasms, Whole Exome Sequencing}, issn = {1600-0560}, doi = {10.1111/cup.13664}, author = {Cheraghlou, Shayan and Atzmony, Lihi and Roy, Simon F and McNiff, Jennifer M and Choate, Keith A} } @article {875, title = {Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {46-59}, abstract = {

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait{\textquoteright}s heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.

}, keywords = {Aged, Cohort Studies, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.004}, author = {Chun, Sung and Imakaev, Maxim and Hui, Daniel and Patsopoulos, Nikolaos A and Neale, Benjamin M and Kathiresan, Sekar and Stitziel, Nathan O and Sunyaev, Shamil R} } @article {927, title = {A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 10 01}, pages = {2904-2910}, abstract = {

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.

}, keywords = {Aged, Asian Continental Ancestry Group, Bilateral Vestibulopathy, Cerebellar Ataxia, Cohort Studies, DNA Repeat Expansion, Female, Humans, Indonesia, Male, Middle Aged, Pedigree, Replication Protein C}, issn = {1460-2156}, doi = {10.1093/brain/awaa263}, author = {Scriba, Carolin K and Beecroft, Sarah J and Clayton, Joshua S and Cortese, Andrea and Sullivan, Roisin and Yau, Wai Yan and Dominik, Natalia and Rodrigues, Miriam and Walker, Elizabeth and Dyer, Zoe and Wu, Teddy Y and Davis, Mark R and Chandler, David C and Weisburd, Ben and Houlden, Henry and Reilly, Mary M and Laing, Nigel G and Lamont, Phillipa J and Roxburgh, Richard H and Ravenscroft, Gianina} } @article {848, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17\% to 78\% for coronary artery disease, 13\% to 76\% for breast cancer, and 11\% to 80\% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {888, title = {Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Am J Clin Nutr}, volume = {112}, year = {2020}, month = {2020 07 01}, pages = {57-65}, abstract = {

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95\% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1~=~2.40; 95\% CI: 1.24, 4.65; P-trend~=~0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1~=~3.15; 95\% CI: 1.75, 5.67; P-trend~<0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1~=~1.98; 95\% CI: 1.09, 3.59; P-trend~=~0.031).

CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

}, keywords = {Adolescent, Adult, Aged, Diabetes Mellitus, Female, Hispanic Americans, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Sphingolipids, United States, Young Adult}, issn = {1938-3207}, doi = {10.1093/ajcn/nqaa114}, author = {Chen, Guo-Chong and Chai, Jin Choul and Yu, Bing and Michelotti, Gregory A and Grove, Megan L and Fretts, Amanda M and Daviglus, Martha L and Garcia-Bedoya, Olga L and Thyagarajan, Bharat and Schneiderman, Neil and Cai, Jianwen and Kaplan, Robert C and Boerwinkle, Eric and Qi, Qibin} } @article {868, title = {Titin Truncating Variants in Adults Without Known Congestive Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {75}, year = {2020}, month = {2020 03 17}, pages = {1239-1241}, keywords = {Adult, Aged, Asymptomatic Diseases, Connectin, Female, Genetic Variation, Heart Failure, Humans, Male, Middle Aged}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.01.013}, author = {Pirruccello, James P and Bick, Alexander and Chaffin, Mark and Aragam, Krishna G and Choi, Seung Hoan and Lubitz, Steven A and Ho, Carolyn Y and Ng, Kenney and Philippakis, Anthony and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {933, title = { truncations cause arrhythmogenic right ventricular cardiomyopathy.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {254-257}, abstract = {

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.

OBJECTIVE: Filamin C gene truncations () have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that could be a novel gene associated with ARVC.

METHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for variants. Available family members were tested for cosegregation.

RESULTS: We identified two unique variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling {\textquoteright}definite{\textquoteright} diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.

CONCLUSION: The identification of as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC disease genes for this disorder. Our findings should prompt inclusion of genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

}, keywords = {Adult, Aged, Arrhythmogenic Right Ventricular Dysplasia, Female, Filamins, Genetic Predisposition to Disease, Genetic Testing, Heart Ventricles, Humans, Male, Middle Aged, Mutation, Phenotype}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106394}, author = {Brun, Francesca and Gigli, Marta and Graw, Sharon L and Judge, Daniel P and Merlo, Marco and Murray, Brittney and Calkins, Hugh and Sinagra, Gianfranco and Taylor, Matthew Rg and Mestroni, Luisa and James, Cynthia A} } @article {853, title = {Validation of a Genome-Wide Polygenic~Score for Coronary Artery~Disease in~South Asians.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 08 11}, pages = {703-714}, abstract = {

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.

METHODS: This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

RESULTS: The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p~<~0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p~<~0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5\% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p~<~0.05 for each).

CONCLUSIONS: The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

}, keywords = {Adult, Aged, Bangladesh, Case-Control Studies, Coronary Artery Disease, Female, Genome-Wide Association Study, Humans, India, Male, Middle Aged, Multifactorial Inheritance}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.06.024}, author = {Wang, Minxian and Menon, Ramesh and Mishra, Sanghamitra and Patel, Aniruddh P and Chaffin, Mark and Tanneeru, Deepak and Deshmukh, Manjari and Mathew, Oshin and Apte, Sanika and Devanboo, Christina S and Sundaram, Sumathi and Lakshmipathy, Praveena and Murugan, Sakthivel and Sharma, Krishna Kumar and Rajendran, Karthikeyan and Santhosh, Sam and Thachathodiyl, Rajesh and Ahamed, Hisham and Balegadde, Aniketh Vijay and Alexander, Thomas and Swaminathan, Krishnan and Gupta, Rajeev and Mullasari, Ajit S and Sigamani, Alben and Kanchi, Muralidhar and Peterson, Andrew S and Butterworth, Adam S and Danesh, John and Di Angelantonio, Emanuele and Naheed, Aliya and Inouye, Michael and Chowdhury, Rajiv and Vedam, Ramprasad L and Kathiresan, Sekar and Gupta, Ravi and Khera, Amit V} } @article {735, title = {Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.}, journal = {Br J Ophthalmol}, volume = {103}, year = {2019}, month = {2019 03}, pages = {390-397}, abstract = {

BACKGROUND/AIMS: To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease~1 (STGD1) studies (ProgStar) and to~determine geographic differences based on the allele frequency.

METHODS: 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.

RESULTS: 211 likely pathogenic variants were identified in the total cohort, including missense (63\%), splice site alteration (18\%), stop (9\%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50\%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15\%), p.G863A (7\%)~and~c.5461-10 T>C (5\%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.

CONCLUSIONS: There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

}, keywords = {Adolescent, Adult, Age of Onset, Aged, ATP-Binding Cassette Transporters, Child, Child, Preschool, Cohort Studies, Databases, Factual, DNA Mutational Analysis, Female, Gene Frequency, Genotyping Techniques, Geography, Humans, Internationality, Macular Degeneration, Male, Middle Aged, Mutation, Polymerase Chain Reaction}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2018-312064}, author = {Fujinami, Kaoru and Strauss, Rupert W and Chiang, John Pei-Wen and Audo, Isabelle S and Bernstein, Paul S and Birch, David G and Bomotti, Samantha M and Cideciyan, Artur V and Ervin, Ann-Margret and Marino, Meghan J and Sahel, Jos{\'e}-Alain and Mohand-Said, Saddek and Sunness, Janet S and Traboulsi, Elias I and West, Sheila and Wojciechowski, Robert and Zrenner, Eberhart and Michaelides, Michel and Scholl, Hendrik P N} } @article {624, title = {Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms.}, journal = {Dev Cell}, volume = {45}, year = {2018}, month = {2018 04 23}, pages = {226-244.e8}, abstract = {

Nuclei are actively positioned and anchored to the cytoskeleton via the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We identified mutations in the Parkin-like E3 ubiquitin ligase Ariadne-1 (Ari-1) that affect the localization and distribution of LINC~complex members in Drosophila. ari-1 mutants exhibit nuclear clustering and morphology defects in larval muscles. We show that Ari-1 mono-ubiquitinates the core LINC complex member Koi. Surprisingly, we discovered functional redundancy between Parkin and Ari-1: increasing Parkin expression rescues ari-1 mutant phenotypes and vice versa. We further show that rare variants in the human homolog of ari-1 (ARIH1) are associated with thoracic aortic aneurysms and dissections, conditions resulting from smooth muscle cell (SMC) dysfunction. Human ARIH1 rescues fly ari-1 mutant phenotypes, whereas human variants found in patients fail to do so. In addition, SMCs obtained from patients display aberrant nuclear morphology. Hence, ARIH1 is critical in anchoring myonuclei to the cytoskeleton.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Animals, Aortic Aneurysm, Carrier Proteins, Cell Nucleus, Child, Preschool, Cytoskeleton, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Male, Middle Aged, Mutation, Myocytes, Smooth Muscle, Pedigree, Phenotype, Ubiquitin-Protein Ligases, Young Adult}, issn = {1878-1551}, doi = {10.1016/j.devcel.2018.03.020}, author = {Tan, Kai Li and Haelterman, Nele A and Kwartler, Callie S and Regalado, Ellen S and Lee, Pei-Tseng and Nagarkar-Jaiswal, Sonal and Guo, Dong-Chuan and Duraine, Lita and Wangler, Michael F and Bamshad, Michael J and Nickerson, Deborah A and Lin, Guang and Milewicz, Dianna M and Bellen, Hugo J} } @article {487, title = {Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.}, journal = {Skelet Muscle}, volume = {8}, year = {2018}, month = {2018 07 30}, pages = {23}, abstract = {

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.

METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.

RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7\% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.

CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dystroglycans, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins, Muscular Dystrophies, Limb-Girdle, Mutation, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2044-5040}, doi = {10.1186/s13395-018-0170-1}, author = {Johnson, Katherine and Bertoli, Marta and Phillips, Lauren and Topf, Ana and Van den Bergh, Peter and Vissing, John and Witting, Nanna and Nafissi, Shahriar and Jamal-Omidi, Shirin and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Potulska-Chromik, Anna and Deconinck, Nicolas and Wallgren-Pettersson, Carina and Strang-Karlsson, Sonja and Colomer, Jaume and Claeys, Kristl G and De Ridder, Willem and Baets, Jonathan and von der Hagen, Maja and Fern{\'a}ndez-Torr{\'o}n, Roberto and Zulaica Ijurco, Miren and Espinal Valencia, Juan Bautista and Hahn, Andreas and Durmus, Hacer and Willis, Tracey and Xu, Liwen and Valkanas, Elise and Mullen, Thomas E and Lek, Monkol and MacArthur, Daniel G and Straub, Volker} } @article {438, title = {ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 02}, pages = {255-265}, abstract = {

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5{\textquoteright} incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C~>~T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A~>~T; c.2579C~>~A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

}, keywords = {Actins, Aged, Cockayne Syndrome, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Female, Genetic Predisposition to Disease, Humans, Lamin Type A, Male, Middle Aged, Pedigree, Xeroderma Pigmentosum}, issn = {1098-1004}, doi = {10.1002/humu.23367}, author = {Mori, Takayasu and Yousefzadeh, Matthew J and Faridounnia, Maryam and Chong, Jessica X and Hisama, Fuki M and Hudgins, Louanne and Mercado, Gabriela and Wade, Erin A and Barghouthy, Amira S and Lee, Lin and Martin, George M and Nickerson, Deborah A and Bamshad, Michael J and Niedernhofer, Laura J and Oshima, Junko} } @article {489, title = {Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.}, journal = {Nature}, volume = {559}, year = {2018}, month = {2018 07}, pages = {350-355}, abstract = {

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50~kb to 249~Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9\%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50\%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

}, keywords = {Adult, Aged, Alleles, Biological Specimen Banks, Chromosome Aberrations, Chromosome Breakage, Chromosome Fragile Sites, Chromosomes, Human, Pair 10, Clone Cells, Female, Health, Hematologic Neoplasms, Hematopoiesis, Humans, Male, Middle Aged, Mosaicism, Penetrance, United Kingdom}, issn = {1476-4687}, doi = {10.1038/s41586-018-0321-x}, author = {Loh, Po-Ru and Genovese, Giulio and Handsaker, Robert E and Finucane, Hilary K and Reshef, Yakir A and Palamara, Pier Francesco and Birmann, Brenda M and Talkowski, Michael E and Bakhoum, Samuel F and McCarroll, Steven A and Price, Alkes L} } @article {496, title = {Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {832-844}, abstract = {

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with \~{}7\% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Sequence, Base Sequence, Epithelial Cells, Family, Female, HSP40 Heat-Shock Proteins, Humans, Loop of Henle, Male, Middle Aged, Mutation, Pedigree, Polycystic Kidney, Autosomal Dominant, TRPP Cation Channels, Uromodulin, Whole Exome Sequencing, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.013}, author = {Cornec-Le Gall, Emilie and Olson, Rory J and Besse, Whitney and Heyer, Christina M and Gainullin, Vladimir G and Smith, Jessica M and Audr{\'e}zet, Marie-Pierre and Hopp, Katharina and Porath, Binu and Shi, Beili and Baheti, Saurabh and Senum, Sarah R and Arroyo, Jennifer and Madsen, Charles D and F{\'e}rec, Claude and Joly, Dominique and Jouret, Fran{\c c}ois and Fikri-Benbrahim, Oussamah and Charasse, Christophe and Coulibaly, Jean-Marie and Yu, Alan S and Khalili, Korosh and Pei, York and Somlo, Stefan and Le Meur, Yannick and Torres, Vicente E and Harris, Peter C} } @article {522, title = {Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 11 01}, pages = {3801-3812}, abstract = {

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value~<~2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value~=~0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

}, keywords = {Adolescent, Adult, Aged, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Whole Exome Sequencing, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddy269}, author = {Qiao, Dandi and Ameli, Asher and Prokopenko, Dmitry and Chen, Han and Kho, Alvin T and Parker, Margaret M and Morrow, Jarrett and Hobbs, Brian D and Liu, Yanhong and Beaty, Terri H and Crapo, James D and Barnes, Kathleen C and Nickerson, Deborah A and Bamshad, Michael and Hersh, Craig P and Lomas, David A and Agusti, Alvar and Make, Barry J and Calverley, Peter M A and Donner, Claudio F and Wouters, Emiel F and Vestbo, J{\o}rgen and Par{\'e}, Peter D and Levy, Robert D and Rennard, Stephen I and Tal-Singer, Ruth and Spitz, Margaret R and Sharma, Amitabh and Ruczinski, Ingo and Lange, Christoph and Silverman, Edwin K and Cho, Michael H} } @article {421, title = {Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.}, journal = {Orphanet J Rare Dis}, volume = {12}, year = {2017}, month = {2017 11 17}, pages = {173}, abstract = {

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants.

RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13~T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease.

CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, alpha-Glucosidases, Child, Child, Preschool, Cohort Studies, Female, Genetic Variation, Glycogen Storage Disease Type II, Humans, Male, Middle Aged, Muscle Weakness, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing, Young Adult}, issn = {1750-1172}, doi = {10.1186/s13023-017-0722-1}, author = {Johnson, Katherine and Topf, Ana and Bertoli, Marta and Phillips, Lauren and Claeys, Kristl G and Stojanovic, Vidosava Rakocevic and Peri{\'c}, Stojan and Hahn, Andreas and Maddison, Paul and Akay, Ela and Bastian, Alexandra E and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Lek, Monkol and Xu, Liwen and MacArthur, Daniel G and Straub, Volker} } @article {387, title = {Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

BACKGROUND: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations.

METHODS AND RESULTS: A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome sequencing. A total of 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59\%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76\% and 40\%, respectively; <0.001). We identified 0, 1, and >=2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of noncompacted to compacted myocardium (<0.001) and left ventricular ejection fraction (=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (=0.004).

CONCLUSIONS: LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or nonsarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Cardiac Myosins, Carrier Proteins, Child, Connectin, Female, Genetic Association Studies, Genetic Variation, Heart Ventricles, Humans, LIM Domain Proteins, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Muscle Proteins, Myocardium, Myosin Heavy Chains, Prospective Studies, Severity of Illness Index, Tropomyosin, Ventricular Dysfunction, Left, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.117.001763}, author = {Miszalski-Jamka, Karol and Jefferies, John L and Mazur, Wojciech and G{\l}owacki, Jan and Hu, Jianhong and Lazar, Monika and Gibbs, Richard A and Liczko, Jacek and K{\l}y{\'s}, Jan and Venner, Eric and Muzny, Donna M and Rycaj, Jaros{\l}aw and Bia{\l}kowski, Jacek and Kluczewska, Ewa and Kalarus, Zbigniew and Jhangiani, Shalini and Al-Khalidi, Hussein and Kukulski, Tomasz and Lupski, James R and Craigen, William J and Bainbridge, Matthew N} } @article {399, title = {Phenotypic spectrum of autosomal recessive congenital ichthyosis due to PNPLA1 mutation.}, journal = {Br J Dermatol}, volume = {177}, year = {2017}, month = {2017 07}, pages = {319-322}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Heterozygote, Homozygote, Humans, Ichthyosis, Infant, Lipase, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.15570}, author = {Boyden, L M and Craiglow, B G and Hu, R H and Zhou, J and Browning, J and Eichenfield, L and Lim, Y L and Luu, M and Randolph, L M and Ginarte, M and Fachal, L and Rodriguez-Pazos, L and Vega, A and Kramer, D and Yosipovitch, G and Vahidnezhad, H and Youssefian, L and Uitto, J and Lifton, R P and Paller, A S and Milstone, L M and Choate, K A} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40\%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30~Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {380, title = {Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 11}, pages = {1246-1252}, abstract = {

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

}, keywords = {Adult, Aged, Antigens, CD, Cadherins, Early Detection of Cancer, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Male, Middle Aged, Sequence Analysis, DNA, Stomach Neoplasms}, issn = {1476-5438}, doi = {10.1038/ejhg.2017.138}, author = {Vogelaar, Ingrid P and van der Post, Rachel S and van Krieken, J Han Jm and Spruijt, Liesbeth and van Zelst-Stams, Wendy Ag and Kets, C Marleen and Lubinski, Jan and Jakubowska, Anna and Teodorczyk, Urszula and Aalfs, Cora M and van Hest, Liselotte P and Pinheiro, Hugo and Oliveira, Carla and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and de Ligt, Joep and Vissers, Lisenka E L M and Hoischen, Alexander and Gilissen, Christian and van de Vorst, Maartje and Goeman, Jelle J and Schackert, Hans K and Ranzani, Guglielmina N and Molinaro, Valeria and G{\'o}mez Garc{\'\i}a, Encarna B and Hes, Frederik J and Holinski-Feder, Elke and Genuardi, Maurizio and Ausems, Margreet G E M and Sijmons, Rolf H and Wagner, Anja and van der Kolk, Lizet E and Bj{\o}rnevoll, Inga and H{\o}berg-Vetti, Hildegunn and van Kessel, Ad Geurts and Kuiper, Roland P and Ligtenberg, Marjolijn J L and Hoogerbrugge, Nicoline} } @article {118, title = {Assessment of estimated retinal atrophy progression in Stargardt macular dystrophy using spectral-domain optical coherence tomography.}, journal = {Br J Ophthalmol}, volume = {100}, year = {2016}, month = {2016 Jul}, pages = {956-962}, abstract = {

AIMS: To estimate disease progression based on analysis of macular volume measured by spectral-domain optical coherence tomography (SD-OCT) in patients affected by Stargardt macular dystrophy (STGD1) and to evaluate the influence of software errors on these measurements.

METHODS: 58 eyes of 29 STGD1 patients were included. Numbers and types of algorithm errors were recorded and manually corrected. In a subgroup of 36 eyes of 18 patients with at least two examinations over time, total macular volume (TMV) and volumes of all nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields were obtained. Random effects models were used to estimate the rate of change per year for the population, and empirical Bayes slopes were used to estimate yearly decline in TMV for individual eyes.

RESULTS: 6958 single B-scans from 190 macular cube scans were analysed. 2360 (33.9\%) showed algorithm errors. Mean observation period for follow-up data was 15 months (range 3-40). The median (IQR) change in TMV using the empirical Bayes estimates for the individual eyes was -0.103 (-0.145, -0.059) mm per year. The mean ({\textpm}SD) TMV was 6.321{\textpm}1.000 mm at baseline, and rate of decline was -0.118 mm per year (p=0.003). Yearly mean volume change was -0.004 mm in the central subfield (mean baseline=0.128 mm), -0.032 mm in the inner (mean baseline=1.484 mm) and -0.079 mm in the outer ETDRS subfields (mean baseline=5.206 mm).

CONCLUSIONS: SD-OCT measurements allow monitoring the decline in retinal volume in STGD1; however, they require significant manual correction of software errors.

}, keywords = {Adolescent, Adult, Aged, Child, Disease Progression, Female, Humans, Macula Lutea, Macular Degeneration, Male, Middle Aged, Reproducibility of Results, Retrospective Studies, Tomography, Optical Coherence, Visual Acuity, Young Adult}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2015-307035}, author = {Strauss, Rupert W and Mu{\~n}oz, Beatriz and Wolfson, Yulia and Sophie, Raafay and Fletcher, Emily and Bittencourt, Millena G and Scholl, Hendrik P N} } @article {52, title = {Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 09}, pages = {470-4}, abstract = {

Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC; p = 0.005) in 1,058 participants from three cohorts: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and Jackson Heart Study (JHS) of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Cohort Studies, Female, Gene Frequency, Genotype, High-Throughput Nucleotide Sequencing, Humans, Leukocyte Count, Male, Middle Aged, Mutation, Missense, National Heart, Lung, and Blood Institute (U.S.), Neutropenia, Neutrophils, Sequence Analysis, DNA, United States, Vacuolar Proton-Translocating ATPases}, issn = {1098-2272}, doi = {10.1002/gepi.21976}, author = {Rosenthal, Elisabeth A and Makaryan, Vahagn and Burt, Amber A and Crosslin, David R and Kim, Daniel Seung and Smith, Joshua D and Nickerson, Deborah A and Reiner, Alex P and Rich, Stephen S and Jackson, Rebecca D and Ganesh, Santhi K and Polfus, Linda M and Qi, Lihong and Dale, David C and Jarvik, Gail P} } @article {344, title = {Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Jan}, pages = {9-19}, abstract = {

Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants and copy number variants that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

}, keywords = {Adult, Aged, ATP-Binding Cassette Transporters, Comparative Genomic Hybridization, DNA Copy Number Variations, Electroretinography, Female, High-Throughput Nucleotide Sequencing, Humans, Macula Lutea, Macular Degeneration, Male, Middle Aged, Mutation, Pedigree, Phenotype}, issn = {1432-1203}, doi = {10.1007/s00439-015-1605-y}, author = {Lee, Winston and Xie, Yajing and Zernant, Jana and Yuan, Bo and Bearelly, Srilaxmi and Tsang, Stephen H and Lupski, James R and Allikmets, Rando} } @article {530, title = {Evidence of macular pigment in the central macula in albinism.}, journal = {Exp Eye Res}, volume = {145}, year = {2016}, month = {2016 04}, pages = {468-471}, abstract = {

PURPOSE: Albinism represents a spectrum of disorders with diminished to absent amounts of melanin pigmentation including the posterior segment of the eye. Macular pigment (MP) consists of two main carotenoids, lutein and zeaxanthin, concentrated in the macula. MP serves as blue light absorbent, antioxidant, and may reduce chromatic aberration and glare. It remains unclear if albinos have detectable MP. The purpose was to investigate the distribution of MP in albino patients with psychophysical and imaging techniques.

METHODS: MP was measured at the eccentricity of 0.5{\textdegree} by heterochromatic flicker perimetry (QuantifEye({\textregistered}); Tinsley Precision Instruments Ltd.) or by scanning laser ophthalmoscopy (MPOD module, MultiColor Spectralis({\textregistered}), Heidelberg Engineering, Heidelberg, Germany) in four albino patients, who were also investigated with multimodal ophthalmic imaging.

RESULTS: Visual acuity ranged from 20/32 to 20/125, nystagmus was present in three patients, and all patients showed typical foveal hypoplasia on fundus exam and optical coherence tomography. Fundus autofluorescence (FAF) demonstrated various degrees of central FAF signal attenuation. Genetic testing was available in three patients and confirmed the diagnosis. Measurable amounts of MP were detected in all four patients and ranged from 0.05 to 0.24, which is below the normal range.

CONCLUSIONS: We conclude that MP can be demonstrated and measured in albinos. Further studies are needed to investigate MP accumulation following carotenoid supplementation and its impact on visual performance.

}, keywords = {Adult, Aged, Albinism, Ocular, Fluorescein Angiography, Humans, Macula Lutea, Macular Pigment, Male, Middle Aged, Tomography, Optical Coherence, Visual Acuity, Visual Field Tests, Visual Fields}, issn = {1096-0007}, doi = {10.1016/j.exer.2015.10.006}, author = {Wolfson, Yulia and Fletcher, Emily and Strauss, Rupert W and Scholl, Hendrik P N} } @article {93, title = {Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.}, journal = {Fam Cancer}, volume = {15}, year = {2016}, month = {2016 Apr}, pages = {281-8}, abstract = {

In up to 30\% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.

}, keywords = {Adenomatous Polyposis Coli, Adenomatous Polyps, Aged, Desmocollins, Exome, Female, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Ion Channels, Male, Middle Aged, Reproducibility of Results}, issn = {1573-7292}, doi = {10.1007/s10689-016-9870-z}, author = {Spier, Isabel and Kerick, Martin and Drichel, Dmitriy and Horpaopan, Sukanya and Altm{\"u}ller, Janine and Laner, Andreas and Holzapfel, Stefanie and Peters, Sophia and Adam, Ronja and Zhao, Bixiao and Becker, Tim and Lifton, Richard P and Holinski-Feder, Elke and Perner, Sven and Thiele, Holger and N{\"o}then, Markus M and Hoffmann, Per and Timmermann, Bernd and Schweiger, Michal R and Aretz, Stefan} } @article {71, title = {Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.}, journal = {Pediatrics}, volume = {137}, year = {2016}, month = {2016 04}, abstract = {

BACKGROUND AND OBJECTIVE: Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).

METHODS: DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing. Multifaceted phenotypes, representing major domains of expressive language functioning, were derived from collected speech samples.

RESULTS: Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 {\texttimes} 10(-7)). The analysis of exome variants revealed coding sequence variants in 14 genes, most of which play a role in neural development. Targeted enrichment analysis implicated myocyte enhancer factor-2 (MEF2)-regulated genes in DLD in the AZ population. The main findings were successfully replicated in an independent cohort of children at risk for related disorders (n = 372).

CONCLUSIONS: MEF2-regulated pathways were identified as potential candidate pathways in the etiology of DLD. Several genes (including the candidate SETBP1 and other MEF2-related genes) seem to jointly influence certain, but not all, facets of the DLD phenotype. Even when genetic and environmental diversity is reduced, DLD is best conceptualized as etiologically complex. Future research should establish whether the signals detected in the AZ population can be replicated in other samples and languages and provide further characterization of the identified pathway.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Exome, Genome-Wide Association Study, Humans, Language Disorders, Middle Aged, Polymorphism, Single Nucleotide, Russia, Sequence Analysis, DNA, Young Adult}, issn = {1098-4275}, doi = {10.1542/peds.2015-2469}, author = {Kornilov, Sergey A and Rakhlin, Natalia and Koposov, Roman and Lee, Maria and Yrigollen, Carolyn and {\c C}a{\u g}layan, Ahmet Okay and Magnuson, James S and Mane, Shrikant and Chang, Joseph T and Grigorenko, Elena L} } @article {8, title = {A germline ERBB3 variant is a candidate for predisposition to erythroid MDS/erythroleukemia.}, journal = {Leukemia}, volume = {30}, year = {2016}, month = {2016 Nov}, pages = {2242-2245}, keywords = {Adult, Aged, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Leukemia, Erythroblastic, Acute, Male, Middle Aged, Myelodysplastic Syndromes, Pedigree, Receptor, ErbB-3}, issn = {1476-5551}, doi = {10.1038/leu.2016.173}, author = {Braunstein, E M and Li, R and Sobreira, N and Marosy, B and Hetrick, K and Doheny, K and Gocke, C D and Valle, D and Brodsky, R A and Cheng, L} } @article {639, title = {Keratoacanthoma Shares Driver Mutations with Cutaneous Squamous Cell Carcinoma.}, journal = {J Invest Dermatol}, volume = {136}, year = {2016}, month = {2016 08}, pages = {1737-1741}, keywords = {Aged, Aged, 80 and over, Biomarkers, Tumor, Biopsy, Carcinoma, Squamous Cell, Cohort Studies, Diagnosis, Differential, Exome, Female, Humans, Keratoacanthoma, Loss of Heterozygosity, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Skin, Skin Neoplasms, Whole Exome Sequencing}, issn = {1523-1747}, doi = {10.1016/j.jid.2016.04.002}, author = {Lim, Young H and Fisher, Jonathan M and Bosenberg, Marcus W and Choate, Keith A and Ko, Christine J} } @article {25, title = {Loss-of-function variants influence the human serum metabolome.}, journal = {Sci Adv}, volume = {2}, year = {2016}, month = {2016 Aug}, pages = {e1600800}, abstract = {

The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45\% difference in geometric mean metabolite levels, with an average effect size of 25\%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.

}, keywords = {Aged, Biomarkers, Black or African American, Exome, Female, Genetic Variation, Heart Failure, High-Throughput Nucleotide Sequencing, Humans, Hypertension, Liver-Specific Organic Anion Transporter 1, Male, Metabolome, Middle Aged, Mutation, Risk Factors, White People}, issn = {2375-2548}, doi = {10.1126/sciadv.1600800}, author = {Yu, Bing and Li, Alexander H and Metcalf, Ginger A and Muzny, Donna M and Morrison, Alanna C and White, Simon and Mosley, Thomas H and Gibbs, Richard A and Boerwinkle, Eric} } @article {87, title = {LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.}, journal = {Circ Res}, volume = {118}, year = {2016}, month = {2016 Mar 18}, pages = {928-34}, abstract = {

RATIONALE: Mutations in several genes have been identified that are responsible for 25\% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75\% of families.

OBJECTIVES: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.

METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.

CONCLUSIONS: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.

}, keywords = {Adult, Aged, Amino Acid Sequence, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Female, Genetic Variation, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Protein-Lysine 6-Oxidase}, issn = {1524-4571}, doi = {10.1161/CIRCRESAHA.115.307130}, author = {Guo, Dong-Chuan and Regalado, Ellen S and Gong, Limin and Duan, Xueyan and Santos-Cortez, Regie Lyn P and Arnaud, Pauline and Ren, Zhao and Cai, Bo and Hostetler, Ellen M and Moran, Rocio and Liang, David and Estrera, Anthony and Safi, Hazim J and Leal, Suzanne M and Bamshad, Michael J and Shendure, Jay and Nickerson, Deborah A and Jondeau, Guillaume and Boileau, Catherine and Milewicz, Dianna M} } @article {119, title = {Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 Feb}, pages = {160-4}, abstract = {

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

}, keywords = {14-3-3 Proteins, Adult, Aged, Alu Elements, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Chromosome Duplication, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Female, Genetic Loci, Genome, Human, Hand Deformities, Congenital, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22929}, author = {Gu, Shen and Posey, Jennifer E and Yuan, Bo and Carvalho, Claudia M B and Luk, H M and Erikson, Kelly and Lo, Ivan F M and Leung, Gordon K C and Pickering, Curtis R and Chung, Brian H Y and Lupski, James R} } @article {111, title = {Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.}, journal = {Clin Genet}, volume = {89}, year = {2016}, month = {2016 06}, pages = {719-23}, abstract = {

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7\%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

}, keywords = {Adult, Aged, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Exome, Family Health, Female, Fibrillin-1, Genetic Predisposition to Disease, Humans, Male, Marfan Syndrome, Middle Aged, Mutation, Pedigree, Sequence Analysis, DNA}, issn = {1399-0004}, doi = {10.1111/cge.12702}, author = {Regalado, E S and Guo, D C and Santos-Cortez, R L P and Hostetler, E and Bensend, T A and Pannu, H and Estrera, A and Safi, H and Mitchell, A L and Evans, J P and Leal, S M and Bamshad, M and Shendure, J and Nickerson, D A and Milewicz, D M} } @article {115, title = {Whole-Exome Sequencing in Familial Parkinson Disease.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 Jan}, pages = {68-75}, abstract = {

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5\% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6\% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

}, keywords = {Adult, Aged, Cohort Studies, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Parkinsonian Disorders, Protein-Tyrosine Kinases, Sequence Analysis, DNA, Tenascin}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.3266}, author = {Farlow, Janice L and Robak, Laurie A and Hetrick, Kurt and Bowling, Kevin and Boerwinkle, Eric and Coban-Akdemir, Zeynep H and Gambin, Tomasz and Gibbs, Richard A and Gu, Shen and Jain, Preti and Jankovic, Joseph and Jhangiani, Shalini and Kaw, Kaveeta and Lai, Dongbing and Lin, Hai and Ling, Hua and Liu, Yunlong and Lupski, James R and Muzny, Donna and Porter, Paula and Pugh, Elizabeth and White, Janson and Doheny, Kimberly and Myers, Richard M and Shulman, Joshua M and Foroud, Tatiana} } @article {180, title = {Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {512-7}, abstract = {

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 {\texttimes} 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 {\texttimes} 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7\% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

}, keywords = {Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Cells, Cultured, DNA Helicases, DNA Mutational Analysis, Exome, Exoribonucleases, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Lod Score, Male, Middle Aged, Molecular Sequence Data, Pedigree, Telomere, Telomere Shortening}, issn = {1546-1718}, doi = {10.1038/ng.3278}, author = {Stuart, Bridget D and Choi, Jungmin and Zaidi, Samir and Xing, Chao and Holohan, Brody and Chen, Rui and Choi, Mihwa and Dharwadkar, Pooja and Torres, Fernando and Girod, Carlos E and Weissler, Jonathan and Fitzgerald, John and Kershaw, Corey and Klesney-Tait, Julia and Mageto, Yolanda and Shay, Jerry W and Ji, Weizhen and Bilguvar, Kaya and Mane, Shrikant and Lifton, Richard P and Garcia, Christine Kim} } @article {202, title = {Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.}, journal = {Int J Cancer}, volume = {137}, year = {2015}, month = {2015 Jul 15}, pages = {320-31}, abstract = {

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5\% (4/266) of all patients, 4\% (3/77) of all familial cases and 7\% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.

}, keywords = {Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Child, Colorectal Neoplasms, DNA Polymerase II, DNA-Directed DNA Polymerase, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Isoenzymes, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Phospholipase D, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult}, issn = {1097-0215}, doi = {10.1002/ijc.29396}, author = {Spier, Isabel and Holzapfel, Stefanie and Altm{\"u}ller, Janine and Zhao, Bixiao and Horpaopan, Sukanya and Vogt, Stefanie and Chen, Sophia and Morak, Monika and Raeder, Susanne and Kayser, Katrin and Stienen, Dietlinde and Adam, Ronja and N{\"u}rnberg, Peter and Plotz, Guido and Holinski-Feder, Elke and Lifton, Richard P and Thiele, Holger and Hoffmann, Per and Steinke, Verena and Aretz, Stefan} } @article {195, title = {Rare variants in RTEL1 are associated with familial interstitial pneumonia.}, journal = {Am J Respir Crit Care Med}, volume = {191}, year = {2015}, month = {2015 Mar 15}, pages = {646-55}, abstract = {

RATIONALE: Up to 20\% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

OBJECTIVES: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

METHODS: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.

MEASUREMENTS AND MAIN RESULTS: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7\%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10\% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.

CONCLUSIONS: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

}, keywords = {Aged, Aged, 80 and over, DNA Helicases, Female, Genetic Variation, Heterozygote, Humans, Lung, Lung Diseases, Interstitial, Male, Middle Aged, Pedigree, Telomere}, issn = {1535-4970}, doi = {10.1164/rccm.201408-1510OC}, author = {Cogan, Joy D and Kropski, Jonathan A and Zhao, Min and Mitchell, Daphne B and Rives, Lynette and Markin, Cheryl and Garnett, Errine T and Montgomery, Keri H and Mason, Wendi R and McKean, David F and Powers, Julia and Murphy, Elissa and Olson, Lana M and Choi, Leena and Cheng, Dong-Sheng and Blue, Elizabeth Marchani and Young, Lisa R and Lancaster, Lisa H and Steele, Mark P and Brown, Kevin K and Schwarz, Marvin I and Fingerlin, Tasha E and Schwartz, David A and Lawson, William E and Loyd, James E and Zhao, Zhongming and Phillips, John A and Blackwell, Timothy S} } @article {246, title = {Attitudes of non-African American focus group participants toward return of results from exome and whole genome sequencing.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2153-60}, abstract = {

Exome sequencing and whole genome sequencing (ES/WGS) present individuals with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, it is unclear which genetic results people want to receive (i.e., what type of genetic information they want to learn about themselves) or conversely not receive, and how they want to receive or manage results over time. Very little is known about whether and how attitudes toward receiving individual results from ES/WGS vary among racial/ethnic populations. We conducted 13 focus groups with a racially and ethnically diverse parent population (n = 76) to investigate attitudes toward return of individual results from WGS. We report on our findings for non-African American (non-AA) participants. Non-AA participants were primarily interested in genetic results on which they could act or "do something about." They defined "actionability" broadly to include individual medical treatment and disease prevention. The ability to plan for the future was both a motivation for and an expected benefit of receiving results. Their concerns focused on the meaning of results, specifically the potential inaccuracy and uncertainty of results. Non-AA participants expected healthcare providers to be involved in results management by helping them interpret results in the context of their own health and by providing counseling support. We compare and contrast these themes with those we previously reported from our analysis of African American (AA) perspectives to highlight the importance of varying preferences for results, characterize the central role of temporal orientation in framing expectations about the possibility of receiving ES/WGS results, and identify potential avenues by which genomic healthcare disparities may be inadvertently perpetuated.

}, keywords = {Adult, African Americans, Aged, Attitude to Health, Exome, Female, Focus Groups, Genome, Human, Humans, Male, Middle Aged, Sequence Analysis, DNA}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36610}, author = {Yu, Joon-Ho and Crouch, Julia and Jamal, Seema M and Bamshad, Michael J and Tabor, Holly K} } @article {221, title = {Informed consent for exome sequencing research in families with genetic disease: the emerging issue of incidental findings.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Nov}, pages = {2745-52}, abstract = {

Genomic sequencing technology is increasingly used in genetic research. Studies of informed consent for exome and genome sequencing (ES/GS) research have largely involved hypothetical scenarios or healthy individuals enrolling in population-based studies. Studies have yet to explore the consent experiences of adults with inherited disease. We conducted a qualitative interview study of 15 adults recently enrolled in a large-scale ES/GS study (11 affected adults, four parents of affected children). Our study had two goals: (1) to explore three theoretical barriers to consent for ES/GS research (interpretive/technical complexity, possibility of incidental findings, and risks of loss of privacy); and (2) to explore how interviewees experienced the consent process. Interviewees could articulate study goals and processes, describe incidental findings, discuss risks of privacy loss, and reflect on their consent experience. Few expected the study would identify the genetic cause of their condition. All elected to receive incidental findings. Interviewees acknowledged paying little attention to potential implications of incidental findings in light of more pressing goals of supporting research regarding their own medical conditions. Interviewees suggested that experience living with a genetic condition prepared them to adjust to incidental findings. Interviewees also expressed little concern about loss of confidentiality of study data. Some experienced the consent process as very long. None desired reconsent prior to return of study results. Families with inherited disease likely would benefit from a consent process in which study risks and benefits were discussed in the context of prior experiences with genetic research and genetic disease.

}, keywords = {Adolescent, Adult, Aged, Confidentiality, Ethics, Medical, Exome, Family, Female, Genetic Diseases, Inborn, Genetic Research, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Informed Consent, Male, Middle Aged, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36706}, author = {Bergner, Amanda L and Bollinger, Juli and Raraigh, Karen S and Tichnell, Crystal and Murray, Brittney and Blout, Carrie Lynn and Telegrafi, Aida Bytyci and James, Cynthia A} } @article {222, title = {Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Oct 02}, pages = {345-59}, abstract = {

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

}, keywords = {Adult, Aged, Aged, 80 and over, Chromosome Aberrations, DNA Copy Number Variations, Fathers, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Inheritance Patterns, Male, Middle Aged, Models, Theoretical, Mosaicism, Mothers, Pregnancy, Recurrence, Risk Factors, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.08.010}, author = {Campbell, Ian M and Stewart, Jonathan R and James, Regis A and Lupski, James R and Stankiewicz, Pawe{\l} and Olofsson, Peter and Shaw, Chad A} } @article {255, title = {Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jun}, pages = {613-7}, abstract = {

Adrenal tumors autonomously producing cortisol cause Cushing{\textquoteright}s syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35\% of adenomas with overt Cushing{\textquoteright}s syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

}, keywords = {Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Amino Acid Sequence, Base Sequence, cdc42 GTP-Binding Protein, Cell Proliferation, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Exome, Female, Gene Deletion, Gene Dosage, HEK293 Cells, Humans, Hydrocortisone, Male, Middle Aged, Molecular Sequence Data, Mutation, Phosphorylation, Sequence Analysis, DNA, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.2956}, author = {Goh, Gerald and Scholl, Ute I and Healy, James M and Choi, Murim and Prasad, Manju L and Nelson-Williams, Carol and Kunstman, John W and Kuntsman, John W and Korah, Reju and Suttorp, Anna-Carinna and Dietrich, Dimo and Haase, Matthias and Willenberg, Holger S and St{\r a}lberg, Peter and Hellman, Per and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Lifton, Richard P} } @article {303, title = {Attitudes of African Americans toward return of results from exome and whole genome sequencing.}, journal = {Am J Med Genet A}, volume = {161A}, year = {2013}, month = {2013 May}, pages = {1064-72}, abstract = {

Exome sequencing and whole genome sequencing (ES/WGS) present patients and research participants with the opportunity to benefit from a broad scope of genetic results of clinical and personal utility. Yet, this potential for benefit also risks disenfranchising populations such as African Americans (AAs) that are already underrepresented in genetic research and utilize genetic tests at lower rates than other populations. Understanding a diverse range of perspectives on consenting for ES/WGS and receiving ES/WGS results is necessary to ensure parity in genomic health care and research. We conducted a series of 13 focus groups (n = 76) to investigate if and how attitudes toward participation in ES/WGS research and return of results from ES/WGS differ between self-described AAs and non-AAs. The majority of both AAs and non-AAs were willing to participate in WGS studies and receive individual genetic results, but the fraction not interested in either was higher in AAs. This is due in part to different expectations of health benefits from ES/WGS and how results should be managed. Our results underscore the need to develop and test culturally tailored strategies for returning ES/WGS results to AAs.

}, keywords = {Adult, African Americans, Aged, Attitude, Exome, Female, Focus Groups, Genetic Research, Genome-Wide Association Study, Humans, Male, Middle Aged, Sequence Analysis, DNA, Surveys and Questionnaires, Washington}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35914}, author = {Yu, Joon-Ho and Crouch, Julia and Jamal, Seema M and Tabor, Holly K and Bamshad, Michael J} } @article {280, title = {Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer.}, journal = {Anesthesiology}, volume = {119}, year = {2013}, month = {2013 Dec}, pages = {1422-33}, abstract = {

BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort.

METHODS: Intensity of cold (+2-4{\textdegree}C) and heat (+48{\textdegree}C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression.

RESULTS: There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found.

CONCLUSIONS: SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied.

}, keywords = {Acute Pain, Adult, Aged, Analgesics, Opioid, Anesthesia, Breast Neoplasms, Catechol O-Methyltransferase, Cold Temperature, Databases, Genetic, Female, Follow-Up Studies, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Hot Temperature, Humans, Middle Aged, Oxycodone, Pain Measurement, Pain, Postoperative, Polymorphism, Single Nucleotide}, issn = {1528-1175}, doi = {10.1097/ALN.0000000000000013}, author = {Kambur, Oleg and Kaunisto, Mari A and Tikkanen, Emmi and Leal, Suzanne M and Ripatti, Samuli and Kalso, Eija A} } @article {317, title = {Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Dec}, pages = {1370-4}, abstract = {

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

}, keywords = {Adult, Aged, Chromosomal Proteins, Non-Histone, Chromosomes, Human, Pair 18, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Haplotypes, Heredity, Homeodomain Proteins, Humans, Male, Middle Aged, Muscular Dystrophy, Facioscapulohumeral, Mutation}, issn = {1546-1718}, doi = {10.1038/ng.2454}, author = {Lemmers, Richard J L F and Tawil, Rabi and Petek, Lisa M and Balog, Judit and Block, Gregory J and Santen, Gijs W E and Amell, Amanda M and van der Vliet, Patrick J and Almomani, Rowida and Straasheijm, Kirsten R and Krom, Yvonne D and Klooster, Rinse and Sun, Yu and den Dunnen, Johan T and Helmer, Quinta and Donlin-Smith, Colleen M and Padberg, George W and van Engelen, Baziel G M and de Greef, Jessica C and Aartsma-Rus, Annemieke M and Frants, Rune R and de Visser, Marianne and Desnuelle, Claude and Sacconi, Sabrina and Filippova, Galina N and Bakker, Bert and Bamshad, Michael J and Tapscott, Stephen J and Miller, Daniel G and van der Maarel, Silv{\`e}re M} }