De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
Jason Homsy,Samir Zaidi,Yufeng Shen,James S. Ware,James S. Ware,James S. Ware,Kaitlin E. Samocha,Konrad J. Karczewski,Steven R. DePalma,Steven R. DePalma,David M. McKean,Hiroko Wakimoto,Josh Gorham,Sheng Chih Jin,John E. Deanfield,Alessandro Giardini,George A. Porter,Richard B. Kim,Kaya Bilguvar,Francesc López-Giráldez,Irina Tikhonova,Shrikant Mane,Angela Romano-Adesman,Hongjian Qi,Hongjian Qi,Badri N. Vardarajan,Lijiang Ma,Mark J. Daly,Amy E. Roberts,Mark W. Russell,Seema Mital,Jane W. Newburger,J. William Gaynor,Roger E. Breitbart,Ivan Iossifov,Michael Ronemus,Stephen Sanders,Jonathan R. Kaltman,Jonathan G. Seidman,Martina Brueckner,Bruce D. Gelb,Elizabeth Goldmuntz,Elizabeth Goldmuntz,Richard P. Lifton,Richard P. Lifton,Christine E. Seidman,Christine E. Seidman,Christine E. Seidman,Wendy K. Chung +48 more
TLDR
Clinical genotyping of patients with CHD may help to identify those at greatest risk of neurodevelopmental disabilities, allowing surveillance and early intervention and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.Abstract:
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.read more
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Journal ArticleDOI
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands
Sheng Chih Jin,Jason Homsy,Samir Zaidi,Qiongshi Lu,Sarah U. Morton,Steven R. DePalma,Xue Zeng,Hongjian Qi,Weni Chang,Michael C. Sierant,Wei Chien Hung,Shozeb Haider,Junhui Zhang,James R. Knight,Robert D. Bjornson,Christopher Castaldi,Irina R. Tikhonoa,Kaya Bilguvar,Shrikant Mane,Stephen Sanders,Seema Mital,Mark W. Russell,J. William Gaynor,John E. Deanfield,Alessandro Giardini,George A. Porter,Deepak Srivastava,Cecelia W. Lo,Yufeng Shen,W. Scott Watkins,Mark Yandell,H. Joseph Yost,Martin Tristani-Firouzi,Jane W. Newburger,Amy E. Roberts,Richard B. Kim,Hongyu Zhao,Jonathan R. Kaltman,Elizabeth Goldmuntz,Wendy K. Chung,Jonathan G. Seidman,Bruce D. Gelb,Christine E. Seidman,Richard P. Lifton,Richard P. Lifton,Martina Brueckner +45 more
TL;DR: Exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent–offspring trios, implicated rare inherited mutations in 1.8%, and DNMs in ∼440 genes were inferred to contribute to CHD.
Journal ArticleDOI
Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association.
Jack Rychik,Andrew M. Atz,David S. Celermajer,Barbara J. Deal,Michael A. Gatzoulis,Marc Gewillig,Tain-Yen Hsia,Daphne T. Hsu,Adrienne H. Kovacs,Brian W. McCrindle,Jane W. Newburger,Nancy A. Pike,Mark D. Rodefeld,David N. Rosenthal,Kurt R. Schumacher,Bradley S. Marino,Karen K. Stout,Gruschen R. Veldtman,Adel K. Younoszai,Yves d'Udekem +19 more
TL;DR: There is a clear need for consensus on how best to follow up patients with Fontan circulation and to treat their complications, and a proposed surveillance testing toolkit provides recommendations for a range of acceptable approaches to follow-up care.
Journal ArticleDOI
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
Holly A.F. Stessman,Bo Xiong,Bo Xiong,Bradley P. Coe,Tianyun Wang,Kendra Hoekzema,Kendra Hoekzema,Michaela Fenckova,Malin Kvarnung,Jennifer Gerdts,Sandy Trinh,Nele Cosemans,Laura Vives,Janice Lin,Tychele N. Turner,Gijs W. E. Santen,Claudia A. L. Ruivenkamp,Marjolein Kriek,Arie van Haeringen,Emmelien Aten,Kathryn Friend,Kathryn Friend,Jan Liebelt,Christopher Barnett,Eric Haan,Eric Haan,Marie Shaw,Jozef Gecz,Jozef Gecz,Jozef Gecz,Britt-Marie Anderlid,Ann Nordgren,Anna Lindstrand,Charles E. Schwartz,R. Frank Kooy,Geert Vandeweyer,Céline Helsmoortel,Corrado Romano,Antonino Alberti,Mirella Vinci,Emanuela Avola,Stefania Giusto,Eric Courchesne,Tiziano Pramparo,Karen Pierce,Srinivasa Nalabolu,David G. Amaral,Ingrid E. Scheffer,Ingrid E. Scheffer,Martin B. Delatycki,Paul J. Lockhart,Fereydoun Hormozdiari,Benjamin Harich,Anna Castells-Nobau,Kun Xia,Hilde Peeters,Magnus Nordenskjöld,Annette Schenck,Raphael Bernier,Evan E. Eichler,Evan E. Eichler +60 more
TL;DR: Twenty-five genes showing a bias for autism versus intellectual disability and a network associated with high-functioning autism are highlighted, and clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.
Journal ArticleDOI
Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.
Mary Ella M Pierpont,Martina Brueckner,Wendy K. Chung,Vidu Garg,Ronald V. Lacro,Amy L. McGuire,Seema Mital,James R. Priest,William T. Pu,Amy E. Roberts,Stephanie M. Ware,Bruce D. Gelb,Mark W. Russell +12 more
TL;DR: This review provides an updated summary of the state of the authors' knowledge of the genetic contributions to the pathogenesis of congenital heart disease and recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies.
Journal ArticleDOI
Single-Cell Resolution of Temporal Gene Expression during Heart Development.
Daniel M. DeLaughter,Alexander G. Bick,Hiroko Wakimoto,David M. McKean,Joshua M. Gorham,Irfan S. Kathiriya,John T. Hinson,Jason Homsy,Jesse M. Gray,William T. Pu,Benoit G. Bruneau,Jonathan G. Seidman,Christine E. Seidman,Christine E. Seidman +13 more
TL;DR: This spatiotemporal transcriptome analysis of heart development reveals lineage-specific gene programs underlying normal cardiac development and congenital heart disease.
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TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Journal ArticleDOI
The contribution of de novo coding mutations to autism spectrum disorder
Ivan Iossifov,Brian J. O'Roak,Stephen Sanders,Stephen Sanders,Michael Ronemus,Niklas Krumm,Dan Levy,Holly A.F. Stessman,Kali Witherspoon,Laura Vives,Karynne E. Patterson,Joshua D. Smith,Bryan W. Paeper,Deborah A. Nickerson,Jeanselle Dea,Shan Dong,Shan Dong,Luis E. Gonzalez,Jeffrey D. Mandell,Shrikant Mane,Michael T. Murtha,Catherine A.W. Sullivan,Michael F. Walker,Zainulabedin Waqar,Liping Wei,A. Jeremy Willsey,A. Jeremy Willsey,Boris Yamrom,Yoon-ha Lee,Ewa A. Grabowska,Ertugrul Dalkic,Ertugrul Dalkic,Zihua Wang,Steven Marks,Peter Andrews,Anthony Leotta,Jude Kendall,Inessa Hakker,Julie Rosenbaum,Beicong Ma,Linda Rodgers,Jennifer Troge,Giuseppe Narzisi,Seungtai Yoon,Michael C. Schatz,Kenny Ye,W. Richard McCombie,Jay Shendure,Evan E. Eichler,Evan E. Eichler,Matthew W. State,Matthew W. State,Michael Wigler +52 more
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Journal ArticleDOI
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Stephen Sanders,Michael T. Murtha,Abha R. Gupta,John D. Murdoch,Melanie J. Raubeson,A. Jeremy Willsey,A. Gulhan Ercan-Sencicek,Nicholas M. DiLullo,Neelroop N. Parikshak,Jason L. Stein,Michael F. Walker,Gordon T. Ober,Nicole A. Teran,Youeun Song,Paul El-Fishawy,Ryan C. Murtha,Murim Choi,John D. Overton,Robert D. Bjornson,Nicholas Carriero,Kyle A. Meyer,Kaya Bilguvar,Shrikant Mane,Nenad Sestan,Richard P. Lifton,Murat Gunel,Kathryn Roeder,Daniel H. Geschwind,Bernie Devlin,Matthew W. State +29 more
TL;DR: It is shown, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects.
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