Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
Sheng Chih JinJason HomsySamir ZaidiQiongshi LuSarah MortonSteven R DePalmaXue ZengHongjian QiWeni ChangMichael C SierantWei-Chien HungShozeb M HaiderJunhui ZhangJames R KnightRobert D BjornsonChristopher CastaldiIrina R TikhonoaKaya BilguvarShrikant M ManeStephan J SandersSeema MitalMark W RussellJ William GaynorJohn DeanfieldAlessandro GiardiniGeorge A PorterDeepak SrivastavaCecelia W LoYufeng ShenW Scott WatkinsMark YandellH Joseph YostMartin Tristani-FirouziJane W NewburgerAmy E RobertsRichard KimHongyu ZhaoJonathan R KaltmanElizabeth GoldmuntzWendy K ChungJonathan G SeidmanBruce D GelbChristine E SeidmanRichard P LiftonMartina BruecknerPublished in: Nature genetics (2017)
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
Keyphrases
- congenital heart disease
- genome wide
- copy number
- dna methylation
- intellectual disability
- genome wide identification
- bioinformatics analysis
- end stage renal disease
- chronic kidney disease
- acute myeloid leukemia
- newly diagnosed
- autism spectrum disorder
- genome wide analysis
- cardiovascular disease
- left ventricular
- heart failure
- transcription factor
- risk factors
- prognostic factors
- cardiovascular events
- tyrosine kinase
- insulin resistance
- metabolic syndrome
- single cell
- early onset