Genomic analyses implicate noncoding de novo variants in congenital heart disease.
Richter F, Morton SU, Kim SW, Kitaygorodsky A, Wasson LK, Chen KM, Zhou J, Qi H, Patel N, DePalma SR, Parfenov M, Homsy J, Gorham JM, Manheimer KB, Velinder M, Farrell A, Marth G, Schadt EE, Kaltman JR, Newburger JW, Giardini A, Goldmuntz E, Brueckner M, Kim R, Porter GA Jr, Bernstein D, Chung WK, Srivastava D, Tristani-Firouzi M, Troyanskaya OG, Dickel DE, Shen Y, Seidman JG, Seidman CE, Gelb BD.
Nat Genet. 2020 Aug;52(8):769-777. doi: 10.1038/s41588-020-0652-z. Epub 2020 Jun 29.
Take Home Points:
- A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs).
- In this National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Cardiac Genomics Consortium (PCGC) study of >13,000 patients with CHD utilizing whole-exome sequencing (WES) and chromosome microarrays rare transmitted variants and DNVs in 8% of patients with sporadic CHD.
- CHD probands and their parents when compared to unaffected trios demonstrated a higher burden of DNVs in individuals with CHD.
- DNV burden was also observed in RNA-binding-protein regulatory sites.
Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric and Fetal Cardiology Journal Watch: In this landmark study National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Cardiac Genomics Consortium (PCGC) recruited >13,000 patients and utilized whole-exome sequencing (WES) and chromosome microarrays to study CHD genetic architecture. The analyses identified damaging rare transmitted variants and DNVs in 8% of patients with sporadic CHD (including 28% of syndromic and 3% of isolated CHD). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. The study also demonstrated DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, P = 8.8 × 10−5).