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Autor(en) / Beteiligte

Titel

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Ist Teil von

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations. Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1 , 2 ). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%) 3 , suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance 4 , 5 . De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations 6 , 7 . We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings 8 . Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4 , CDK13 and PRKD1 . Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Sprache: Englisch
Identifikatoren: ISSN: 1061-4036
eISSN: 1546-1718
DOI: 10.1038/ng.3627
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5988037

Format: –
Schlagworte: 45, 45/23, 45/43, 631/208/2489, 692/308/2056, 692/699/75/1539, Agriculture, Animal Genetics and Genomics, Autism, Autoantigens - genetics, Biomedical research, Biomedicine, Cancer Research, CDC2 Protein Kinase - chemistry, CDC2 Protein Kinase - genetics, Congenital diseases, Congenital heart defects, Defects, Development and progression, Exome - genetics, Exome sequencing, Female, Funding, Gene Function, Genes, Genetic aspects, Genetic variation, Genomes, Genomics, Health aspects, Heart, Heart Defects, Congenital - genetics, Human Genetics, Humans, Identification and classification, Kinases, letter, Male, Medical research, Methods, Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics, Mutation, Mutation - genetics, Protein Conformation, Protein Kinase C - genetics, RNA polymerase, Sequence Deletion, Syndrome

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