@article {923, title = {Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {119-133}, abstract = {

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48\%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26\%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61926}, author = {Dyment, David A and O{\textquoteright}Donnell-Luria, Anne and Agrawal, Pankaj B and Coban Akdemir, Zeynep and Aleck, Kyrieckos A and Antaki, Danny and Al Sharhan, Hind and Au, Ping-Yee B and Aydin, Hatip and Beggs, Alan H and Bilguvar, Kaya and Boerwinkle, Eric and Brand, Harrison and Brownstein, Catherine A and Buyske, Steve and Chodirker, Bernard and Choi, Jungmin and Chudley, Albert E and Clericuzio, Carol L and Cox, Gerald F and Curry, Cynthia and de Boer, Elke and de Vries, Bert B A and Dunn, Kathryn and Dutmer, Cullen M and England, Eleina M and Fahrner, Jill A and Geckinli, Bilgen B and Genetti, Casie A and Gezdirici, Alper and Gibson, William T and Gleeson, Joseph G and Greenberg, Cheryl R and Hall, April and Hamosh, Ada and Hartley, Taila and Jhangiani, Shalini N and Karaca, Ender and Kernohan, Kristin and Lauzon, Julie L and Lewis, M E Suzanne and Lowry, R Brian and L{\'o}pez-Gir{\'a}ldez, Francesc and Matise, Tara C and McEvoy-Venneri, Jennifer and McInnes, Brenda and Mhanni, Aziz and Garcia Minaur, Sixto and Moilanen, Jukka and Nguyen, An and Nowaczyk, Malgorzata J M and Posey, Jennifer E and {\~O}unap, Katrin and Pehlivan, Davut and Pajusalu, Sander and Penney, Lynette S and Poterba, Timothy and Prontera, Paolo and Doriqui, Maria Juliana Rodovalho and Sawyer, Sarah L and Sobreira, Nara and Stanley, Valentina and Torun, Deniz and Wargowski, David and Witmer, P Dane and Wong, Isaac and Xing, Jinchuan and Zaki, MAH S and Zhang, Yeting and Boycott, Kym M and Bamshad, Michael J and Nickerson, Deborah A and Blue, Elizabeth E and Innes, A Micheil} } @article {950, title = {8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 03 23}, pages = {1523}, abstract = {

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

}, keywords = {Aged, Case-Control Studies, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Mutation, Prostatic Neoplasms, Protective Factors, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-15122-1}, author = {Dupont, William D and Breyer, Joan P and Plummer, W Dale and Chang, Sam S and Cookson, Michael S and Smith, Joseph A and Blue, Elizabeth E and Bamshad, Michael J and Smith, Jeffrey R} } @article {809, title = {Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1406}, abstract = {

BACKGROUND: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5\%-2\%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20\%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

METHODS: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12\% BAV, 29\% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63\% TAD, 34\% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

RESULTS: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18\%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p~<~.003).

CONCLUSION: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.

}, keywords = {Adult, Aortic Aneurysm, Thoracic, Bicuspid Aortic Valve Disease, Female, GATA4 Transcription Factor, Gene Frequency, Humans, Male, Middle Aged, Mutation, Receptor, Notch1, Receptors, Cell Surface, Smad6 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1406}, author = {Musfee, Fadi I and Guo, Dongchuan and Pinard, Am{\'e}lie C and Hostetler, Ellen M and Blue, Elizabeth E and Nickerson, Deborah A and Bamshad, Michael J and Milewicz, Dianna M and Prakash, Siddharth K} } @article {666, title = {Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.}, journal = {Birth Defects Res}, volume = {111}, year = {2019}, month = {2019 Dec 01}, pages = {1618-1632}, abstract = {

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child{\textquoteright}s father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens.

METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA.

RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol.

CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

}, issn = {2472-1727}, doi = {10.1002/bdr2.1554}, author = {Jenkins, Mary M and Almli, Lynn M and Pangilinan, Faith and Chong, Jessica X and Blue, Elizabeth E and Shapira, Stuart K and White, Janson and McGoldrick, Daniel and Smith, Joshua D and Mullikin, James C and Bean, Christopher J and Nembhard, Wendy N and Lou, Xiang-Yang and Shaw, Gary M and Romitti, Paul A and Keppler-Noreuil, Kim and Yazdy, Mahsa M and Kay, Denise M and Carter, Tonia C and Olshan, Andrew F and Moore, Kristin J and Nascone-Yoder, Nanette and Finnell, Richard H and Lupo, Philip J and Feldkamp, Marcia L and Nickerson, Deborah A and Bamshad, Michael J and Brody, Lawrence C and Reefhuis, Jennita} } @article {674, title = {Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 10}, pages = {1813-1825}, abstract = {

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70\% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30\%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

}, issn = {1098-1004}, doi = {10.1002/humu.23793}, author = {Cox, Timothy C and Lidral, Andrew C and McCoy, Jason C and Liu, Huan and Cox, Liza L and Zhu, Ying and Anderson, Ryan D and Moreno Uribe, Lina M and Anand, Deepti and Deng, Mei and Richter, Chika T and Nidey, Nichole L and Standley, Jennifer M and Blue, Elizabeth E and Chong, Jessica X and Smith, Joshua D and Kirk, Edwin P and Venselaar, Hanka and Krahn, Katy N and van Bokhoven, Hans and Zhou, Huiqing and Cornell, Robert A and Glass, Ian A and Bamshad, Michael J and Nickerson, Deborah A and Murray, Jeffrey C and Lachke, Salil A and Thompson, Thomas B and Buckley, Michael F and Roscioli, Tony} }