De novo mutations in Congenital Heart Disease with Neurodevelopmental and Other Birth Defects
Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2015-12, Vol.350 (6265), p.1262-1266 |
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| creator | Homsy, Jason Zaidi, Samir Shen, Yufeng Ware, James S. Samocha, Kaitlin E. Karczewski, Konrad J. DePalma, Steven R. McKean, David Wakimoto, Hiroko Gorham, Josh Jin, Sheng Chih Deanfield, John Giardini, Alessandro Porter, George A. Kim, Richard Bilguvar, Kaya Lopez, Francesc Tikhonova, Irina Mane, Shrikant Romano-Adesman, Angela Qi, Hongjian Vardarajan, Badri Ma, Lijiang Daly, Mark Roberts, Amy E. Russell, Mark W. Mital, Seema Newburger, Jane W. Gaynor, J. William Breitbart, Roger E. Iossifov, Ivan Ronemus, Michael Sanders, Stephan J. Kaltman, Jonathan R. Seidman, Jonathan G. Brueckner, Martina Gelb, Bruce D. Goldmuntz, Elizabeth Lifton, Richard P. Seidman, Christine E. Chung, Wendy K. |
| description | Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging
de novo
mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in
RBFOX2
, an mRNA splice regulator. Genes mutated in other cohorts ascertained 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. |
| doi_str_mv | 10.1126/science.aac9396 |
| format | Article |
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de novo
mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in
RBFOX2
, an mRNA splice regulator. Genes mutated in other cohorts ascertained 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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aac9396</identifier><identifier>PMID: 26785492</identifier><language>eng</language><ispartof>Science (American Association for the Advancement of Science), 2015-12, Vol.350 (6265), p.1262-1266</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids></links><search><creatorcontrib>Homsy, Jason</creatorcontrib><creatorcontrib>Zaidi, Samir</creatorcontrib><creatorcontrib>Shen, Yufeng</creatorcontrib><creatorcontrib>Ware, James S.</creatorcontrib><creatorcontrib>Samocha, Kaitlin E.</creatorcontrib><creatorcontrib>Karczewski, Konrad J.</creatorcontrib><creatorcontrib>DePalma, Steven R.</creatorcontrib><creatorcontrib>McKean, David</creatorcontrib><creatorcontrib>Wakimoto, Hiroko</creatorcontrib><creatorcontrib>Gorham, Josh</creatorcontrib><creatorcontrib>Jin, Sheng Chih</creatorcontrib><creatorcontrib>Deanfield, John</creatorcontrib><creatorcontrib>Giardini, Alessandro</creatorcontrib><creatorcontrib>Porter, George A.</creatorcontrib><creatorcontrib>Kim, Richard</creatorcontrib><creatorcontrib>Bilguvar, Kaya</creatorcontrib><creatorcontrib>Lopez, Francesc</creatorcontrib><creatorcontrib>Tikhonova, Irina</creatorcontrib><creatorcontrib>Mane, Shrikant</creatorcontrib><creatorcontrib>Romano-Adesman, Angela</creatorcontrib><creatorcontrib>Qi, Hongjian</creatorcontrib><creatorcontrib>Vardarajan, Badri</creatorcontrib><creatorcontrib>Ma, Lijiang</creatorcontrib><creatorcontrib>Daly, Mark</creatorcontrib><creatorcontrib>Roberts, Amy E.</creatorcontrib><creatorcontrib>Russell, Mark W.</creatorcontrib><creatorcontrib>Mital, Seema</creatorcontrib><creatorcontrib>Newburger, Jane W.</creatorcontrib><creatorcontrib>Gaynor, J. William</creatorcontrib><creatorcontrib>Breitbart, Roger E.</creatorcontrib><creatorcontrib>Iossifov, Ivan</creatorcontrib><creatorcontrib>Ronemus, Michael</creatorcontrib><creatorcontrib>Sanders, Stephan J.</creatorcontrib><creatorcontrib>Kaltman, Jonathan R.</creatorcontrib><creatorcontrib>Seidman, Jonathan G.</creatorcontrib><creatorcontrib>Brueckner, Martina</creatorcontrib><creatorcontrib>Gelb, Bruce D.</creatorcontrib><creatorcontrib>Goldmuntz, Elizabeth</creatorcontrib><creatorcontrib>Lifton, Richard P.</creatorcontrib><creatorcontrib>Seidman, Christine E.</creatorcontrib><creatorcontrib>Chung, Wendy K.</creatorcontrib><title>De novo mutations in Congenital Heart Disease with Neurodevelopmental and Other Birth Defects</title><title>Science (American Association for the Advancement of Science)</title><description>Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging
de novo
mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in
RBFOX2
, an mRNA splice regulator. Genes mutated in other cohorts ascertained for NDD were enriched in CHD cases, particularly those with coexisting NDD. 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de novo
mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in
RBFOX2
, an mRNA splice regulator. Genes mutated in other cohorts ascertained 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.</abstract><pmid>26785492</pmid><doi>10.1126/science.aac9396</doi></addata></record> |
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| source | JSTOR Archive Collection A-Z Listing; American Association for the Advancement of Science |
| title | De novo mutations in Congenital Heart Disease with Neurodevelopmental and Other Birth Defects |
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