D’Alessandro, Lisa C.A.Al Turki, SaeedManickaraj, Ashok KumarManase, DorinMulder, Barbara J.M.Bergin, LynnRosenberg, Herschel C.Mondal, TapasGordon, ElaineLougheed, JaneSmythe, JohnDevriendt, KoenBhattacharya, ShoumoWatkins, HughBentham, JamieBowdin, SarahHurles, Matthew E.Mital, Seema2018-07-252018D’Alessandro, L. C., S. Al Turki, A. K. Manickaraj, D. Manase, B. J. Mulder, L. Bergin, H. C. Rosenberg, et al. 2018. “Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect.” Genetics in medicine : official journal of the American College of Medical Genetics 18 (2): 189-198. doi:10.1038/gim.2015.60. http://dx.doi.org/10.1038/gim.2015.60.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298209Purpose 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 non-syndromic 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 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, 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.en-USwhole exome sequencingtargeted sequencingatrioventricular septal defectendocardial cushion defectatrioventricular canal defectcongenital heart diseaseCornelia de Lange syndromeCHARGE syndromeJournal Article2018-07-2510.1038/gim.2015.60