TY - JOUR
T1 - Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect
AU - D'Alessandro, Lisa C. A.
AU - Al Turki, Saeed
AU - Manickaraj, Ashok Kumar
AU - Manase, Dorin
AU - Mulder, Barbara J. M.
AU - Bergin, Lynn
AU - Rosenberg, Herschel C.
AU - Mondal, Tapas
AU - Gordon, Elaine
AU - Lougheed, Jane
AU - Smythe, John
AU - Devriendt, Koen
AU - Bhattacharya, Shoumo
AU - Watkins, Hugh
AU - Bentham, Jamie
AU - Bowdin, Sarah
AU - Hurles, Matthew E.
AU - Mital, Seema
PY - 2016
Y1 - 2016
N2 - The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort
AB - The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort
U2 - https://doi.org/10.1038/gim.2015.60
DO - https://doi.org/10.1038/gim.2015.60
M3 - Article
C2 - 25996639
SN - 1098-3600
VL - 18
SP - 189
EP - 198
JO - Genetics in medicine
JF - Genetics in medicine
IS - 2
ER -