Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
Sifrim A., Hitz MP., Wilsdon A., Breckpot J., Turki SH., Thienpont B., McRae J., Fitzgerald TW., Singh T., Swaminathan GJ., Prigmore E., Rajan D., Abdul-Khaliq H., Banka S., Bauer UM., Bentham J., Berger F., Bhattacharya S., Bu'Lock F., Canham N., Colgiu IG., Cosgrove C., Cox H., Daehnert I., Daly A., Danesh J., Fryer A., Gewillig M., Hobson E., Hoff K., Homfray T., Kahlert AK., Ketley A., Kramer HH., Lachlan K., Lampe AK., Louw JJ., Manickara AK., Manase D., McCarthy KP., Metcalfe K., Moore C., Newbury-Ecob R., Omer SO., Ouwehand WH., Park SM., Parker MJ., Pickardt T., Pollard MO., Robert L., Roberts DJ., Sambrook J., Setchfield K., Stiller B., Thornborough C., Toka O., Watkins H., Williams D., Wright M., Mital S., Daubeney PE., Keavney B., Goodship J., Abu-Sulaiman RM., Klaassen S., Wright CF., Firth HV., Barrett JC., Devriendt K., FitzPatrick DR., Brook JD., Hurles ME.
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%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. 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. 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.