@article {900, title = {Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.}, journal = {Hum Mutat}, volume = {42}, year = {2021}, month = {2021 May}, pages = {577-591}, abstract = {

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80\% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

}, issn = {1098-1004}, doi = {10.1002/humu.24190}, author = {Khayat, Michael M and Li, He and Chander, Varuna and Hu, Jianhong and Hansen, Adam W and Li, Shoudong and Traynelis, Josh and Shen, Hua and Weissenberger, George and Stossi, Fabio and Johnson, Hannah L and Lupski, James R and Posey, Jennifer E and Sabo, Aniko and Meng, Qingchang and Murdock, David R and Wangler, Michael and Gibbs, Richard A} } @article {886, title = {Community-based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1439}, abstract = {

BACKGROUND: Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation.

METHODS: Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family.

RESULTS: All five families enrolled in the study opted-in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow-up in an appointment with a board certified clinical geneticist.

CONCLUSION: Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing-based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID.

}, keywords = {Adult, Female, Genetic Testing, Humans, Independent Living, Intellectual Disability, Male, Mediator Complex, Membrane Proteins, Nuclear Proteins, Patient Selection, Sensitivity and Specificity, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {2324-9269}, doi = {10.1002/mgg3.1439}, author = {Sabo, Aniko and Murdock, David and Dugan, Shannon and Meng, Qingchang and Gingras, Marie-Claude and Hu, Jianhong and Muzny, Donna and Gibbs, Richard} } @article {852, title = {Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 07 25}, abstract = {

Approximately 30\% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected cohort of 134 individuals with regressive autism. In total, 16 variants in 12 genes with evidence supportive of pathogenicity were identified. They were classified as variants of uncertain significance based on ACMG standards and guidelines. Among these were recurring variants in and , variants in genes that were linked to syndromic forms of ASD (, , , , , and ), and variants in the form of oligogenic heterozygosity (, , and ).

}, keywords = {Autism Spectrum Disorder, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mutation}, issn = {2073-4425}, doi = {10.3390/genes11080853}, author = {Yin, Jiani and Chun, Chun-An and Zavadenko, Nikolay N and Pechatnikova, Natalia L and Naumova, Oxana Yu and Doddapaneni, Harsha V and Hu, Jianhong and Muzny, Donna M and Schaaf, Christian P and Grigorenko, Elena L} } @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 {588, title = {Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 09}, pages = {2135-2144}, abstract = {

PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by~Multiplex Ligation-dependent Probe Amplification (MLPA).

CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0475-4}, author = {Chiang, Theodore and Liu, Xiuping and Wu, Tsung-Jung and Hu, Jianhong and Sedlazeck, Fritz J and White, Simon and Schaid, Daniel and Andrade, Mariza de and Jarvik, Gail P and Crosslin, David and Stanaway, Ian and Carrell, David S and Connolly, John J and Hakonarson, Hakon and Groopman, Emily E and Gharavi, Ali G and Fedotov, Alexander and Bi, Weimin and Leduc, Magalie S and Murdock, David R and Jiang, Yunyun and Meng, Linyan and Eng, Christine M and Wen, Shu and Yang, Yaping and Muzny, Donna M and Boerwinkle, Eric and Salerno, William and Venner, Eric and Gibbs, Richard A} } @article {563, title = {Genetic architecture of laterality defects revealed by whole exome sequencing.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Apr}, pages = {563-573}, abstract = {

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20\% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1\% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0307-z}, author = {Li, Alexander H and Hanchard, Neil A and Azamian, Mahshid and D{\textquoteright}Alessandro, Lisa C A and Coban-Akdemir, Zeynep and Lopez, Keila N and Hall, Nancy J and Dickerson, Heather and Nicosia, Annarita and Fernbach, Susan and Boone, Philip M and Gambin, Tomaz and Karaca, Ender and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Doddapaneni, HarshaVardhan and Hu, Jianhong and Dinh, Huyen and Jayaseelan, Joy and Muzny, Donna and Lalani, Seema and Towbin, Jeffrey and Penny, Daniel and Fraser, Charles and Martin, James and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Ware, Stephanie M and Belmont, John W} } @article {672, title = {The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {132-150}, abstract = {

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2\% (58/89) of families. Eleven out of 58 families (19.0\%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.015}, author = {Pehlivan, Davut and Bayram, Yavuz and Gunes, Nilay and Coban Akdemir, Zeynep and Shukla, Anju and Bierhals, Tatjana and Tabakci, Burcu and Sahin, Yavuz and Gezdirici, Alper and Fatih, Jawid M and Gulec, Elif Yilmaz and Yesil, G{\"o}zde and Punetha, Jaya and Ocak, Zeynep and Grochowski, Christopher M and Karaca, Ender and Albayrak, Hatice Mutlu and Radhakrishnan, Periyasamy and Erdem, Haktan Bagis and Sahin, Ibrahim and Yildirim, Timur and Bayhan, Ilhan A and Bursali, Aysegul and Elmas, Muhsin and Yuksel, Zafer and Ozdemir, Ozturk and Silan, Fatma and Yildiz, Onur and Yesilbas, Osman and Isikay, Sedat and Balta, Burhan and Gu, Shen and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Tsiakas, Konstantinos and Hempel, Maja and Girisha, Katta Mohan and Gul, Davut and Posey, Jennifer E and Elcioglu, Nursel H and Tuysuz, Beyhan and Lupski, James R} } @article {584, title = {Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.}, journal = {Cell}, volume = {176}, year = {2019}, month = {2019 03 07}, pages = {1310-1324.e10}, abstract = {

DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to \~{}1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.01.045}, author = {Beck, Christine R and Carvalho, Claudia M B and Akdemir, Zeynep C and Sedlazeck, Fritz J and Song, Xiaofei and Meng, Qingchang and Hu, Jianhong and Doddapaneni, Harsha and Chong, Zechen and Chen, Edward S and Thornton, Philip C and Liu, Pengfei and Yuan, Bo and Withers, Marjorie and Jhangiani, Shalini N and Kalra, Divya and Walker, Kimberly and English, Adam C and Han, Yi and Chen, Ken and Muzny, Donna M and Ira, Grzegorz and Shaw, Chad A and Gibbs, Richard A and Hastings, P J and Lupski, James R} } @article {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @article {357, title = {Lessons learned from additional research analyses of unsolved clinical exome cases.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 03 21}, pages = {26}, abstract = {

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36\% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51\% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6\%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6\%), 1/1 multiplex family involving three affected siblings, and 3/4 (75\%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

}, keywords = {Adenosine Triphosphatases, ATPases Associated with Diverse Cellular Activities, Computational Biology, DNA Copy Number Variations, DNA-Binding Proteins, Exome, Female, Genetic Diseases, Inborn, Genomics, GTP-Binding Protein beta Subunits, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mitochondrial Proteins, Pilot Projects, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcription Factors}, issn = {1756-994X}, doi = {10.1186/s13073-017-0412-6}, author = {Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Harel, Tamar and Rosenfeld, Jill A and Gambin, Tomasz and Stray-Pedersen, Asbj{\o}rg and K{\"u}ry, S{\'e}bastien and Mercier, Sandra and Lessel, Davor and Denecke, Jonas and Wiszniewski, Wojciech and Penney, Samantha and Liu, Pengfei and Bi, Weimin and Lalani, Seema R and Schaaf, Christian P and Wangler, Michael F and Bacino, Carlos A and Lewis, Richard Alan and Potocki, Lorraine and Graham, Brett H and Belmont, John W and Scaglia, Fernando and Orange, Jordan S and Jhangiani, Shalini N and Chiang, Theodore and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Xia, Fan and Beaudet, Arthur L and Boerwinkle, Eric and Eng, Christine M and Plon, Sharon E and Sutton, V Reid and Gibbs, Richard A and Posey, Jennifer E and Yang, Yaping and Lupski, James R} } @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 {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 {540, title = {Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 12 04}, pages = {e173438}, abstract = {

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children{\textquoteright}s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7\%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0\%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8\%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9\%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1\%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

}, keywords = {Adult, Critical Care, Disease Management, Exome, Genetic Counseling, Genetic Diseases, Inborn, Humans, Infant, Infant Care, Infant, Newborn, Intensive Care Units, Pediatric, Length of Stay, Retrospective Studies, Texas, Whole Exome Sequencing}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.3438}, author = {Meng, Linyan and Pammi, Mohan and Saronwala, Anirudh and Magoulas, Pilar and Ghazi, Andrew Ray and Vetrini, Francesco and Zhang, Jing and He, Weimin and Dharmadhikari, Avinash V and Qu, Chunjing and Ward, Patricia and Braxton, Alicia and Narayanan, Swetha and Ge, Xiaoyan and Tokita, Mari J and Santiago-Sim, Teresa and Dai, Hongzheng and Chiang, Theodore and Smith, Hadley and Azamian, Mahshid S and Robak, Laurie and Bostwick, Bret L and Schaaf, Christian P and Potocki, Lorraine and Scaglia, Fernando and Bacino, Carlos A and Hanchard, Neil A and Wangler, Michael F and Scott, Daryl and Brown, Chester and Hu, Jianhong and Belmont, John W and Burrage, Lindsay C and Graham, Brett H and Sutton, Vernon Reid and Craigen, William J and Plon, Sharon E and Lupski, James R and Beaudet, Arthur L and Gibbs, Richard A and Muzny, Donna M and Miller, Marcus J and Wang, Xia and Leduc, Magalie S and Xiao, Rui and Liu, Pengfei and Shaw, Chad and Walkiewicz, Magdalena and Bi, Weimin and Xia, Fan and Lee, Brendan and Eng, Christine M and Yang, Yaping and Lalani, Seema R} } @article {39, title = {Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.}, journal = {BMC Med Genomics}, volume = {9}, year = {2016}, month = {2016 Jul 19}, pages = {42}, abstract = {

BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases.

METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher.

RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8~\%) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90~\%.

CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity.

TRIAL REGISTRATION: Not applicable.

}, keywords = {Arabs, Cohort Studies, Consanguinity, Data Mining, Databases, Genetic, DNA Copy Number Variations, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Molecular Diagnostic Techniques, Nervous System Diseases, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1755-8794}, doi = {10.1186/s12920-016-0208-3}, author = {Charng, Wu-Lin and Karaca, Ender and Coban Akdemir, Zeynep and Gambin, Tomasz and Atik, Mehmed M and Gu, Shen and Posey, Jennifer E and Jhangiani, Shalini N and Muzny, Donna M and Doddapaneni, Harsha and Hu, Jianhong and Boerwinkle, Eric and Gibbs, Richard A and Rosenfeld, Jill A and Cui, Hong and Xia, Fan and Manickam, Kandamurugu and Yang, Yaping and Faqeih, Eissa A and Al Asmari, Ali and Saleh, Mohammed A M and El-Hattab, Ayman W and Lupski, James R} }