Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect Journal Articles uri icon

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  • PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


  • D’Alessandro, Lisa CA
  • Al Turki, Saeed
  • Manickaraj, Ashok Kumar
  • Manase, Dorin
  • Mulder, Barbara JM
  • Bergin, Lynn
  • Rosenberg, Herschel C
  • Mondal, Tapas
  • Gordon, Elaine
  • Lougheed, Jane
  • Smythe, John
  • Devriendt, Koen
  • Bhattacharya, Shoumo
  • Watkins, Hugh
  • Bentham, Jamie
  • Bowdin, Sarah
  • Hurles, Matthew E
  • Mital, Seema

publication date

  • February 2016