@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 {838, title = {What Is Familial Hypercholesterolemia, and Why Does It Matter?}, journal = {Circulation}, volume = {141}, year = {2020}, month = {2020 06 02}, pages = {1760-1763}, keywords = {Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Humans, Hyperlipoproteinemia Type II, Prevalence}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.120.046961}, author = {Khera, Amit V and Hegele, Robert A} } @article {752, title = {Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.}, journal = {Kidney Int}, volume = {97}, year = {2020}, month = {2020 03}, pages = {567-579}, abstract = {

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70\% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59\%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2019.09.026}, author = {Jobst-Schwan, Tilman and Kl{\"a}mbt, Verena and Tarsio, Maureen and Heneghan, John F and Majmundar, Amar J and Shril, Shirlee and Buerger, Florian and Ottlewski, Isabel and Shmukler, Boris E and Topaloglu, Rezan and Hashmi, Seema and Hafeez, Farkhanda and Emma, Francesco and Greco, Marcella and Laube, Guido F and Fathy, Hanan M and Pohl, Martin and Gellermann, Jutta and Milosevic, Danko and Baum, Michelle A and Mane, Shrikant and Lifton, Richard P and Kane, Patricia M and Alper, Seth L and Hildebrandt, Friedhelm} } @article {947, title = {Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in .}, journal = {Acta Cardiol}, volume = {75}, year = {2020}, month = {2020 Dec}, pages = {748-753}, abstract = {

Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 40 different genes. Apart from encoding the giant protein Titin, none of these genes have an expected diagnostic yield of more than 5\% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We report on WES in a large family with autosomal dominant DCM complicated by end stage heart failure and non-sustained ventricular arrhythmias in whom no causative mutation was identified using a targeted gene panel including 28 genes. WES was applied on 2 affected cousins. Stringent filtering of the identified genetic variants was performed including population variant frequencies, in silico analysis, orthologous and paralogous conservation. Subsequently Sanger sequencing was performed for 10 potential disease causing variants in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T > A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to arrhythmogenic dilated cardiomyopathy caused by defective splicing of the giant sarcomere protein titin and abnormal calcium handling. We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.

}, issn = {1784-973X}, doi = {10.1080/00015385.2019.1674490}, author = {Robyns, Tomas and Willems, Rik and Van Cleemput, Johan and Jhangiani, Shalini and Muzny, Donna and Gibbs, Richard and Lupski, James R and Breckpot, Jeroen and Devriendt, Koenraad and Corveleyn, Anniek} } @article {858, title = {Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.}, journal = {Clin Genet}, volume = {98}, year = {2020}, month = {2020 11}, pages = {477-485}, abstract = {

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1\%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3\%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50\% of them.

}, issn = {1399-0004}, doi = {10.1111/cge.13823}, author = {Minardi, Raffaella and Licchetta, Laura and Baroni, Maria Chiara and Pippucci, Tommaso and Stipa, Carlotta and Mostacci, Barbara and Severi, Giulia and Toni, Francesco and Bergonzini, Luca and Carelli, Valerio and Seri, Marco and Tinuper, Paolo and Bisulli, Francesca} } @article {761, title = {Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 06}, pages = {1387-1399}, abstract = {

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.

RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6\% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF <= 0.005) with CADD score >= 25 in genes linked to AF in cases compared to controls (P = .0023).

CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

}, keywords = {Adolescent, Adult, AMP-Activated Protein Kinases, Ankyrins, Atrial Fibrillation, Carrier Proteins, Child, Cohort Studies, Cytoskeletal Proteins, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Atria, Homeodomain Proteins, Humans, LIM Domain Proteins, Male, Mutation, Transcription Factors, Whole Exome Sequencing, Wolff-Parkinson-White Syndrome, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61571}, author = {Coban-Akdemir, Zeynep H and Charng, Wu-Lin and Azamian, Mahshid and Paine, Ingrid S and Punetha, Jaya and Grochowski, Christopher M and Gambin, Tomasz and Valdes, Santiago O and Cannon, Bryan and Zapata, Gladys and Hernandez, Patricia P and Jhangiani, Shalini and Doddapaneni, Harsha and Hu, Jianhong and Boricha, Fatima and Muzny, Donna M and Boerwinkle, Eric and Yang, Yaping and Gibbs, Richard A and Posey, Jennifer E and Wehrens, Xander H T and Belmont, John W and Kim, Jeffrey J and Miyake, Christina Y and Lupski, James R and Lalani, Seema R} } @article {596, title = {Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.}, journal = {J Am Soc Nephrol}, volume = {30}, year = {2019}, month = {2019 02}, pages = {201-215}, abstract = {

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20\% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients.

METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children{\textquoteright}s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD.

RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7\%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients.

CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

}, keywords = {Adolescent, Boston, Child, Child, Preschool, Cohort Studies, Female, Genetic Predisposition to Disease, Genetic Testing, Graft Rejection, Graft Survival, Hospitals, Pediatric, Humans, Kidney Transplantation, Male, Precision Medicine, Prognosis, Renal Insufficiency, Chronic, Retrospective Studies, Risk Assessment, Severity of Illness Index, Survival Analysis, Transplant Recipients, Treatment Outcome, Whole Exome Sequencing}, issn = {1533-3450}, doi = {10.1681/ASN.2018060575}, author = {Mann, Nina and Braun, Daniela A and Amann, Kassaundra and Tan, Weizhen and Shril, Shirlee and Connaughton, Dervla M and Nakayama, Makiko and Schneider, Ronen and Kitzler, Thomas M and van der Ven, Amelie T and Chen, Jing and Ityel, Hadas and Vivante, Asaf and Majmundar, Amar J and Daga, Ankana and Warejko, Jillian K and Lovric, Svjetlana and Ashraf, Shazia and Jobst-Schwan, Tilman and Widmeier, Eugen and Hugo, Hannah and Mane, Shrikant M and Spaneas, Leslie and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Stein, Deborah R and Baum, Michelle A and Daouk, Ghaleb H and Lifton, Richard P and Manzi, Shannon and Vakili, Khashayar and Kim, Heung Bae and Rodig, Nancy M and Hildebrandt, Friedhelm} } @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 {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {630, title = {Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {13}, year = {2018}, month = {2018 01 06}, pages = {53-62}, abstract = {

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30\% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

RESULTS: In 74 of 300 families (25\%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7\%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38\% of consanguineous families and in 13\% of nonconsanguineous families, and 48\% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. , , , and were the most common genes in which we detected a mutation. In another 28\% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

}, issn = {1555-905X}, doi = {10.2215/CJN.04120417}, author = {Warejko, Jillian K and Tan, Weizhen and Daga, Ankana and Schapiro, David and Lawson, Jennifer A and Shril, Shirlee and Lovric, Svjetlana and Ashraf, Shazia and Rao, Jia and Hermle, Tobias and Jobst-Schwan, Tilman and Widmeier, Eugen and Majmundar, Amar J and Schneider, Ronen and Gee, Heon Yung and Schmidt, J Magdalena and Vivante, Asaf and van der Ven, Amelie T and Ityel, Hadas and Chen, Jing and Sadowski, Carolin E and Kohl, Stefan and Pabst, Werner L and Nakayama, Makiko and Somers, Michael J G and Rodig, Nancy M and Daouk, Ghaleb and Baum, Michelle and Stein, Deborah R and Ferguson, Michael A and Traum, Avram Z and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan and Zenker, Martin and Bakkaloglu, Sevcan A and M{\"u}ller, Dominik and Noyan, Aytul and Ozaltin, Fatih and Cadnapaphornchai, Melissa A and Hashmi, Seema and Hopcian, Jeffrey and Kopp, Jeffrey B and Benador, Nadine and Bockenhauer, Detlef and Bogdanovic, Radovan and Staji{\'c}, Natasa and Chernin, Gil and Ettenger, Robert and Fehrenbach, Henry and Kemper, Markus and Munarriz, Reyner Loza and Podracka, Ludmila and B{\"u}scher, Rainer and Serdaroglu, Erkin and Tasic, Velibor and Mane, Shrikant and Lifton, Richard P and Braun, Daniela A and Hildebrandt, Friedhelm} } @article {497, title = {Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43\% of 35 Families With Midaortic Syndrome.}, journal = {Hypertension}, volume = {71}, year = {2018}, month = {2018 04}, pages = {691-699}, abstract = {

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9\%), we detected likely causal dominant mutations. In 15 of 35 (42.9\%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (, , , , and ). Ten of the 15 mutations have not previously been reported. This is the first report of , , or mutations in individuals with MAS. Mutations were detected in (6/15 families), (4/15 families), (3/15 families), and one family each for and Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

}, keywords = {Adolescent, Aorta, Abdominal, Aortic Valve Stenosis, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Hypertension, Jagged-1 Protein, Male, Mutation, Neurofibromatoses, Neurofibromin 1, Pedigree, Syndrome, United States, Whole Exome Sequencing}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.10296}, author = {Warejko, Jillian K and Schueler, Markus and Vivante, Asaf and Tan, Weizhen and Daga, Ankana and Lawson, Jennifer A and Braun, Daniela A and Shril, Shirlee and Amann, Kassaundra and Somers, Michael J G and Rodig, Nancy M and Baum, Michelle A and Daouk, Ghaleb and Traum, Avram Z and Kim, Heung Bae and Vakili, Khashayar and Porras, Diego and Lock, James and Rivkin, Michael J and Chaudry, Gulraiz and Smoot, Leslie B and Singh, Michael N and Smith, Edward R and Mane, Shrikant M and Lifton, Richard P and Stein, Deborah R and Ferguson, Michael A and Hildebrandt, Friedhelm} } @article {516, title = {Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Sep}, pages = {2348-2361}, abstract = {

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12\% of patients with CAKUT.

METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.

RESULTS: In 29 families (13\%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient{\textquoteright}s CAKUT phenotype. In three families (1\%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8\%).

CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14\% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121265}, author = {van der Ven, Amelie T and Connaughton, Dervla M and Ityel, Hadas and Mann, Nina and Nakayama, Makiko and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Schulz, Julian and Braun, Daniela A and Schmidt, Johanna Magdalena and Schapiro, David and Schneider, Ronen and Warejko, Jillian K and Daga, Ankana and Majmundar, Amar J and Tan, Weizhen and Jobst-Schwan, Tilman and Hermle, Tobias and Widmeier, Eugen and Ashraf, Shazia and Amar, Ali and Hoogstraaten, Charlotte A and Hugo, Hannah and Kitzler, Thomas M and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Spaneas, Leslie and Amann, Kassaundra and Stein, Deborah R and Baum, Michelle A and Somers, Michael J G and Rodig, Nancy M and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Bogdanovic, Radovan and Staji{\'c}, Natasa and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan M and Milosevic, Danko and Al-Saffar, Muna and Awad, Hazem S and Eid, Loai A and Selvin, Aravind and Senguttuvan, Prabha and Sanna-Cherchi, Simone and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Wilson, Michael W and Mane, Shrikant M and Lifton, Richard P and Lee, Richard S and Bauer, Stuart B and Lu, Weining and Reutter, Heiko M and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {492, title = {Whole-exome sequencing identifies mutations in in a mild form of Carey-Fineman-Ziter syndrome.}, journal = {Neurol Genet}, volume = {4}, year = {2018}, month = {2018 Apr}, pages = {e226}, issn = {2376-7839}, doi = {10.1212/NXG.0000000000000226}, author = {Alrohaif, Hadil and Topf, Ana and Evangelista, Teresinha and Lek, Monkol and McArthur, Daniel and Lochm{\"u}ller, Hanns} } @article {385, title = {Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.}, journal = {J Dent Res}, volume = {97}, year = {2018}, month = {2018 Jan}, pages = {49-59}, abstract = {

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

}, keywords = {Anodontia, Female, Genetic Linkage, Genetic Variation, Humans, Intercellular Signaling Peptides and Proteins, Laminin, Low Density Lipoprotein Receptor-Related Protein-6, Male, Membrane Proteins, Mutation, Missense, Pedigree, Real-Time Polymerase Chain Reaction, Turkey, Whole Exome Sequencing, Wnt Proteins}, issn = {1544-0591}, doi = {10.1177/0022034517724149}, author = {Dinckan, N and Du, R and Petty, L E and Coban-Akdemir, Z and Jhangiani, S N and Paine, I and Baugh, E H and Erdem, A P and Kayserili, H and Doddapaneni, H and Hu, J and Muzny, D M and Boerwinkle, E and Gibbs, R A and Lupski, J R and Uyguner, Z O and Below, J E and Letra, A} } @article {446, title = {WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 01 04}, pages = {27-43}, abstract = {

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, \~{}70\% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

}, keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Chromosome Segregation, Craniofacial Abnormalities, Diagnosis, Differential, Dwarfism, Female, Genes, Dominant, Genetic Association Studies, Genetic Heterogeneity, Humans, Limb Deformities, Congenital, Male, Middle Aged, Mutation, Missense, Phenotype, Urogenital Abnormalities, Wnt Signaling Pathway}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.10.002}, author = {White, Janson J and Mazzeu, Juliana F and Coban-Akdemir, Zeynep and Bayram, Yavuz and Bahrambeigi, Vahid and Hoischen, Alexander and van Bon, Bregje W M and Gezdirici, Alper and Gulec, Elif Yilmaz and Ramond, Francis and Touraine, Renaud and Thevenon, Julien and Shinawi, Marwan and Beaver, Erin and Heeley, Jennifer and Hoover-Fong, Julie and Durmaz, Ceren D and Karabulut, Halil Gurhan and Marzioglu-Ozdemir, Ebru and Cayir, Atilla and Duz, Mehmet B and Seven, Mehmet and Price, Susan and Ferreira, Barbara Merfort and Vianna-Morgante, Angela M and Ellard, Sian and Parrish, Andrew and Stals, Karen and Flores-Daboub, Josue and Jhangiani, Shalini N and Gibbs, Richard A and Brunner, Han G and Sutton, V Reid and Lupski, James R and Carvalho, Claudia M B} } @article {425, title = {Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 10 31}, pages = {95}, abstract = {

BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes.

METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs.

RESULTS: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95\% confidence interval 2.5-6.5).

CONCLUSIONS: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

}, keywords = {Female, Genetic Heterogeneity, Heart Defects, Congenital, Humans, Inheritance Patterns, Male, Whole Exome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0482-5}, author = {Li, Alexander H and Hanchard, Neil A and Furthner, Dieter and Fernbach, Susan and Azamian, Mahshid and Nicosia, Annarita and Rosenfeld, Jill and Muzny, Donna and D{\textquoteright}Alessandro, Lisa C A and Morris, Shaine and Jhangiani, Shalini and Parekh, Dhaval R and Franklin, Wayne J and Lewin, Mark and Towbin, Jeffrey A and Penny, Daniel J and Fraser, Charles D and Martin, James F and Eng, Christine and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Belmont, John W} } @article {19, title = {Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 Apr}, pages = {412-420}, abstract = {

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5\% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

}, keywords = {Adolescent, Child, Child, Preschool, DNA Copy Number Variations, Exome Sequencing, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Nuclear Proteins, PAX2 Transcription Factor, Pedigree, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases, Repressor Proteins, Urogenital Abnormalities, Vesico-Ureteral Reflux, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2016.131}, author = {Bekheirnia, Mir Reza and Bekheirnia, Nasim and Bainbridge, Matthew N and Gu, Shen and Coban Akdemir, Zeynep Hande and Gambin, Tomek and Janzen, Nicolette K and Jhangiani, Shalini N and Muzny, Donna M and Michael, Mini and Brewer, Eileen D and Elenberg, Ewa and Kale, Arundhati S and Riley, Alyssa A and Swartz, Sarah J and Scott, Daryl A and Yang, Yaping and Srivaths, Poyyapakkam R and Wenderfer, Scott E and Bodurtha, Joann and Applegate, Carolyn D and Velinov, Milen and Myers, Angela and Borovik, Lior and Craigen, William J and Hanchard, Neil A and Rosenfeld, Jill A and Lewis, Richard Alan and Gonzales, Edmond T and Gibbs, Richard A and Belmont, John W and Roth, David R and Eng, Christine and Braun, Michael C and Lupski, James R and Lamb, Dolores J} } @article {379, title = {Whole-Exome Sequencing Reveals Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report.}, journal = {Mol Syndromol}, volume = {8}, year = {2017}, month = {2017 Aug}, pages = {272-277}, abstract = {

We present the case of a patient of Macedonian origin with unilateral renal agenesis and ureterovesical junction obstruction in combination with further abnormalities including midface hypoplasia, scoliosis as well as camptodactyly of one toe. Whole-exome sequencing analysis revealed compound heterozygous variants in the gene. Recessive variants in are a known cause of van Maldergem syndrome (VMS) in which congenital anomalies of the kidney and urinary tract are a less characteristic but common feature. The initial presentation of our patient was not clinically recognizable. However, in view of the molecular findings, the most likely diagnosis is a mild manifestation of VMS. Only very few publications have reported patients with VMS and mutations in to date. With this case, we hope to provide further insight into the phenotypic variability of this syndrome.

}, issn = {1661-8769}, doi = {10.1159/000477750}, author = {van der Ven, Amelie T and Shril, Shirlee and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Laricchia, Kristen M and Lek, Monkol and Tasic, Velibor and Hildebrandt, Friedhelm} } @article {7, title = {Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 Feb}, pages = {180-192}, abstract = {

Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48\% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4\%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15\% of the interchromosomal translocation events.

}, keywords = {Base Sequence, Chromosome Breakage, Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Genetic Association Studies, Genomics, Genotype, Homologous Recombination, Humans, In Situ Hybridization, Fluorescence, Karyotype, Male, Phenotype, Translocation, Genetic, Whole Genome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23146}, author = {Nilsson, Daniel and Pettersson, Maria and Gustavsson, Peter and F{\"o}rster, Alisa and Hofmeister, Wolfgang and Wincent, Josephine and Zachariadis, Vasilios and Anderlid, Britt-Marie and Nordgren, Ann and M{\"a}kitie, Outi and Wirta, Valtteri and K{\"a}ller, Max and Vezzi, Francesco and Lupski, James R and Nordenskj{\"o}ld, Magnus and Lundberg, Elisabeth Syk and Carvalho, Claudia M B and Lindstrand, Anna} } @article {124, title = {Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity.}, journal = {Kidney Int}, volume = {89}, year = {2016}, month = {2016 Feb}, pages = {468-475}, abstract = {

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

}, keywords = {Age of Onset, Cohort Studies, DNA Mutational Analysis, Exome, Humans, Kidney Diseases, Cystic, Renal Insufficiency, Chronic}, issn = {1523-1755}, doi = {10.1038/ki.2015.317}, author = {Braun, Daniela A and Schueler, Markus and Halbritter, Jan and Gee, Heon Yung and Porath, Jonathan D and Lawson, Jennifer A and Airik, Rannar and Shril, Shirlee and Allen, Susan J and Stein, Deborah and Al Kindy, Adila and Beck, Bodo B and Cengiz, Nurcan and Moorani, Khemchand N and Ozaltin, Fatih and Hashmi, Seema and Sayer, John A and Bockenhauer, Detlef and Soliman, Neveen A and Otto, Edgar A and Lifton, Richard P and Hildebrandt, Friedhelm} } @article {413, title = {Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2016}, month = {2016 01}, pages = {79-84}, abstract = {

Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals. PNPT1 encodes the polynucleotide phosphorylase (PNPase) protein, which is involved in the transport of small RNAs into the mitochondria. These RNAs are involved in the mitochondrial translation machinery, responsible for the synthesis of mitochondrially encoded subunits of the oxidative phosphorylation (OXPHOS) complexes. Both PNPT1 variants are within highly conserved regions and predicted to be damaging. These variants resulted in quaternary defects in the PNPase protein and a clear reduction in protein and mRNA expression of PNPT1 in patient fibroblasts compared with control cells. Protein analysis of the OXPHOS complexes showed a significant reduction in complex I (CI), complex III (CIII) and complex IV (CIV). Enzyme activity of CI and CIV was clearly reduced in patient fibroblasts compared with controls along with a 33\% reduction in total mitochondrial protein synthesis. In vitro rescue experiments, using exogenous expression of wild-type PNPT1 in patient fibroblasts, ameliorated the deficiencies in the OXPHOS complex protein expression, supporting the likely pathogenicity of these variants and the importance of WES in efficiently identifying rare genetic disease genes.

}, keywords = {Axons, Exome, Exoribonucleases, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability, Male, Mitochondria, Mutation, Optic Atrophy, Oxidative Phosphorylation, Pedigree, Protein Structure, Quaternary}, issn = {1476-5438}, doi = {10.1038/ejhg.2016.128}, author = {Alodaib, Ahmad and Sobreira, Nara and Gold, Wendy A and Riley, Lisa G and Van Bergen, Nicole J and Wilson, Meredith J and Bennetts, Bruce and Thorburn, David R and Boehm, Corinne and Christodoulou, John} } @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 {192, title = {Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull{\textquoteright}s Eye Maculopathy.}, journal = {Ophthalmic Genet}, volume = {36}, year = {2015}, month = {2015}, pages = {270-5}, abstract = {

BACKGROUND: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.

MATERIALS AND METHODS: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull{\textquoteright}s eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull{\textquoteright}s eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.

RESULTS: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.

CONCLUSIONS: In summary, a unique case of an adult patient with bull{\textquoteright}s eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

}, keywords = {Adult, Carrier Proteins, Electroretinography, Exome, Female, Genetic Testing, Heterozygote, Homocystinuria, Humans, Macular Degeneration, Mutation, Pedigree, Scotoma, Sequence Analysis, DNA, Tomography, Optical Coherence, Visual Acuity, Visual Fields, Vitamin B 12, Vitamin B 12 Deficiency, Vitamin B Complex}, issn = {1744-5094}, doi = {10.3109/13816810.2015.1010736}, author = {Collison, Frederick T and Xie, Yajing Angela and Gambin, Tomasz and Jhangiani, Shalini and Muzny, Donna and Gibbs, Richard and Lupski, James R and Fishman, Gerald A and Allikmets, Rando} } @article {172, title = {Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Aug}, pages = {1796-806}, abstract = {

Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome.

}, keywords = {Caveolin 1, Cells, Cultured, Exome, Female, Heterozygote, Humans, Infant, Newborn, Lipodystrophy, Male, Mutation, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37115}, author = {Garg, Abhimanyu and Kircher, Martin and Del Campo, Miguel and Amato, R Stephen and Agarwal, Anil K} } @article {218, title = {Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Jan}, pages = {E140-7}, abstract = {

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5\% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined.

OBJECTIVE: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk-characteristic clinical diagnostic findings of PSIS.

DESIGN AND PARTICIPANTS: WES was applied to two affected and one unaffected siblings.

RESULTS: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein-coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell.

CONCLUSION: Mutations of GPR161 may be implicated as a potential novel cause of PSIS.

}, keywords = {Adolescent, Child, Preschool, Exome, Female, Genome-Wide Association Study, Humans, Hypopituitarism, Mutation, Pituitary Gland, Receptors, G-Protein-Coupled}, issn = {1945-7197}, doi = {10.1210/jc.2014-1984}, author = {Karaca, Ender and Buyukkaya, Ramazan and Pehlivan, Davut and Charng, Wu-Lin and Yaykasli, Kursat O and Bayram, Yavuz and Gambin, Tomasz and Withers, Marjorie and Atik, Mehmed M and Arslanoglu, Ilknur and Bolu, Semih and Erdin, Serkan and Buyukkaya, Ayla and Yaykasli, Emine and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R} } @article {165, title = {Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia.}, journal = {Fertil Steril}, volume = {104}, year = {2015}, month = {2015 Aug}, pages = {286-91}, abstract = {

OBJECTIVE: To investigate the genetic cause of nonobstructive azoospermia (NOA) in a consanguineous Turkish family through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations.

DESIGN: Whole-exome sequencing (WES).

SETTING: Research laboratory.

PATIENT(S): Two siblings in a consanguineous family with NOA.

INTERVENTION(S): Validating all variants passing filter criteria with Sanger sequencing to confirm familial segregation and absence in the control population.

MAIN OUTCOME MEASURE(S): Discovery of a mutation that could potentially cause NOA.

RESULT(S): A novel nonsynonymous mutation in the neuronal PAS-2 domain (NPAS2) was identified in a consanguineous family from Turkey. This mutation in exon 14 (chr2: 101592000 C>G) of NPAS2 is likely a disease-causing mutation as it is predicted to be damaging, it is a novel variant, and it segregates with the disease. Family segregation of the variants showed the presence of the homozygous mutation in the three brothers with NOA and a heterozygous mutation in the mother as well as one brother and one sister who were both fertile. The mutation is not found in the single-nucleotide polymorphism database, the 1000 Genomes Project, the Baylor College of Medicine cohort of 500 Turkish patients (not a population-specific polymorphism), or the matching 50 fertile controls.

CONCLUSION(S): With the use of WES we identified a novel homozygous mutation in NPAS2 as a likely disease-causing variant in a Turkish family diagnosed with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases for which conventional genetic approaches have previously failed to find a molecular diagnosis.

}, keywords = {Adult, Azoospermia, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Exome, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Pedigree}, issn = {1556-5653}, doi = {10.1016/j.fertnstert.2015.04.001}, author = {Ramasamy, Ranjith and Bak{\i}rc{\i}o{\u g}lu, M Emre and Cengiz, Cenk and Karaca, Ender and Scovell, Jason and Jhangiani, Shalini N and Akdemir, Zeynep C and Bainbridge, Matthew and Yu, Yao and Huff, Chad and Gibbs, Richard A and Lupski, James R and Lamb, Dolores J} } @article {276, title = {Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.}, journal = {J Med Genet}, volume = {51}, year = {2014}, month = {2014 Mar}, pages = {197-202}, abstract = {

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown.

METHODS: We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both.

RESULTS: In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15\% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*).

CONCLUSIONS: Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.

}, keywords = {Amino Acid Sequence, DNA Mutational Analysis, Exome, Female, GATA6 Transcription Factor, Hernia, Diaphragmatic, Hernias, Diaphragmatic, Congenital, Humans, Male, Molecular Sequence Data, Mutation, Sequence Alignment, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2013-101989}, author = {Yu, Lan and Bennett, James T and Wynn, Julia and Carvill, Gemma L and Cheung, Yee Him and Shen, Yufeng and Mychaliska, George B and Azarow, Kenneth S and Crombleholme, Timothy M and Chung, Dai H and Potoka, Douglas and Warner, Brad W and Bucher, Brian and Lim, Foong-Yen and Pietsch, John and Stolar, Charles and Aspelund, Gudrun and Arkovitz, Marc S and Mefford, Heather and Chung, Wendy K} } @article {233, title = {Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2328-34}, abstract = {

GAPO syndrome (OMIM$\#$230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy. About 35 cases have been reported, making it among one of the rarest recessive conditions. Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype. While this genomic study was in progress mutations in ANTXR1 were reported to cause GAPO syndrome. In our study we performed whole exome sequencing (WES) for five affected individuals from three Turkish kindreds segregating the GAPO trait. Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene. Our studies expand the allelic spectrum in this rare condition and potentially provide insight into the role of ANTXR1 in the regulation of the extracellular matrix.

}, keywords = {Adolescent, Adult, Alopecia, Anodontia, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Facies, Family, Female, Growth Disorders, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Proteins, Optic Atrophies, Hereditary, Pedigree, Protein Structure, Tertiary, Receptors, Cell Surface}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36678}, author = {Bayram, Yavuz and Pehlivan, Davut and Karaca, Ender and Gambin, Tomasz and Jhangiani, Shalini N and Erdin, Serkan and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna and Elcioglu, Nursel H and Yildirim, M Selman and Bozkurt, Banu and Zamani, Ayse Gul and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {272, title = {Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.}, journal = {Eur J Hum Genet}, volume = {22}, year = {2014}, month = {2014 Sep}, pages = {1145-8}, abstract = {

Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM$\#$213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM$\#$614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.

}, keywords = {Abnormalities, Multiple, Exome, Humans, Infant, Intellectual Disability, Male, Membrane Proteins, Mutation, Protein Isoforms}, issn = {1476-5438}, doi = {10.1038/ejhg.2013.291}, author = {Pehlivan, Davut and Karaca, Ender and Aydin, Hatip and Beck, Christine R and Gambin, Tomasz and Muzny, Donna M and Bilge Geckinli, B and Karaman, Ali and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R} } @article {259, title = {Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {59}, year = {2014}, month = {2014 Jul}, pages = {17-21}, abstract = {

Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

}, keywords = {Colitis, DNA Mutational Analysis, Exome, Female, Humans, Hypertriglyceridemia, Infant, Receptors, Lipoprotein}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000000363}, author = {Gonzaga-Jauregui, Claudia and Mir, Sabina and Penney, Samantha and Jhangiani, Shalini and Midgen, Craig and Finegold, Milton and Muzny, Donna M and Wang, Min and Bacino, Carlos A and Gibbs, Richard A and Lupski, James R and Kellermayer, Richard and Hanchard, Neil A} } @article {312, title = {Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum.}, journal = {Clin Genet}, volume = {84}, year = {2013}, month = {2013 Oct}, pages = {394-5}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Consanguinity, Exome, Humans, Male, Membrane Proteins, Pedigree, Phenotype, Sequence Analysis, DNA, Syndrome}, issn = {1399-0004}, doi = {10.1111/cge.12088}, author = {Caglayan, A O and Per, H and Akgumus, G and Gumus, H and Baranoski, J and Canpolat, M and Calik, M and Yikilmaz, A and Bilguvar, K and Kumandas, S and Gunel, M} } @article {318, title = {Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 Mar}, pages = {827-830}, keywords = {Adolescent, Adult, Amino Acid Sequence, Biopsy, Child, Child, Preschool, Cohort Studies, Epidermis, Exome, Humans, Infant, Middle Aged, Molecular Sequence Data, Mutation, Nevus, Sebaceous of Jadassohn, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Sequence Analysis, DNA, Young Adult}, issn = {1523-1747}, doi = {10.1038/jid.2012.379}, author = {Levinsohn, Jonathan L and Tian, Li C and Boyden, Lynn M and McNiff, Jennifer M and Narayan, Deepak and Loring, Erin S and Yun, Duri and Sugarman, Jeffrey L and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Paller, Amy S and Wagner, Annette M and Antaya, Richard J and Choate, Keith A} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }