De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot

SC Greenway, AC Pereira, JC Lin, SR DePalma… - Nature …, 2009 - nature.com
SC Greenway, AC Pereira, JC Lin, SR DePalma, SJ Israel, SM Mesquita, E Ergul, JH Conta…
Nature genetics, 2009nature.com
Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs
sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a
genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11
de novo copy number variants (CNVs) that were absent or extremely rare (< 0.1%) in 2,265
controls. We then examined a second, independent TOF cohort (n= 398) for additional CNVs
at these loci. We identified CNVs at chromosome 1q21. 1 in 1%(5/512, P= 0.0002, OR …
Abstract
Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5–15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.
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