Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands
By S. Jin, Jason G. Homsy, Samir Zaidi, Q. Lu, S. Morton, S. DePalma, Xue Zeng, Hongjian Qi, Weni Chang, M. Sierant and 35 more. Nature Genetics, 2017
773 citations recorded by the source corpus.
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.
Subfields: Epidemiology, Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/4c0a57cd61865f152d6552d112a0740ea8396f88
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In Genetics
- Anne H. O'Donnell-Luria
- Konrad J. Karczewski
- Daniel G. MacArthur
- Jessica Alföldi
- Beryl B. Cummings
- J. Kosmicki
- Matthew Solomonson
In Molecular Biology
Citations in the corpus
- Transcript expression-aware annotation improves rare variant discovery and interpretation (2019, background): “…): N = 51, DDD( 24 ): n = 4,293, Lelieveld et al( 26 ): n = 820), 1,073 probands with congenital heart disease with co-morbid developmental delay (Sifrim et al( 42 ): n = 512, Chih Jin et al( 47 ) : 561), 6,430 ASD probands, and 2,179 unaffected controls from the Autism Sequencing Consortium( 25 ).”
- Variant interpretation using population databases: lessons from gnomAD (2021, methodology): “The gnomAD database has also aided in the discovery of genes associated with many diseases, including neurodevelopmental and congenital heart disorders (The Deciphering Developmental Disorders Study 2015; Jin et al., 2017; Kaplanis et al., 2020; Kosmicki et al., 2017).”