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

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. A genome-wide survey of 114 TOF patients and their unaffected parents identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. A second, independent TOF cohort (n = 398) was then examined for additional CNVs at these loci. In 1% (5/512, p = 0.0002, OR = 22.3) of non-syndromic sporadic TOF cases we identified CNVs at chromosome 1q21.1. Recurrent CNVs were also identified at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single TOF case occurred at six loci, two that encode known (NOTCH1, JAG1) disease genes. Our data predicts that at least 10% (4.5–15.5, 95% CI) of sporadic, non-syndromic TOF reflects de novo CNVs and implicates mutations within these loci as etiologic in other cases of TOF.

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

“…Interestingly, examination of the families reported in the original publication linking NOTCH1 mutations and congenital heart defects demonstrates the presence of an individual with tetralogy of Fallot, a phenotype consistent with the phenotype observed in the Notch1 +/− ;Nos3 −/− embryos 18. This potential link was further supported by the identification of a microdeletion encompassing NOTCH1 in a patient with tetralogy of Fallot by chromosomal microarray 18, 40. Further recent evidence supporting a link between NOTCH1 mutations and right‐sided congenital heart defect is the identification of mutations in NOTCH1 in 2 additional families with malformations of right‐sided cardiac structures 41, 42.…”

1q21.1 Microduplication expression in adults

“…1,2,[5][6][7][8][9][10][11][12] We also examined primary articles and reviews of CNVs in autism, 13 schizophrenia, 14 mental retardation, 15 and congenital heart disease 16 for references to studies reporting subjects with 1q21.1 duplications. [17][18][19][20] Other citations involving 1q21.1 duplication cases were also assessed.…”

“…3,35 We systematically reviewed 28 primary reports identified and their accompanying supplemental materials to identify unique individuals and abstract as much information as possible on each subject. 1,2,[5][6][7][8][9][10][11][12][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Any subjects with 1q21.1 duplications that were not 1.0-5.0 Mb (Figure 1) in size were excluded, 12,31 allowing us to include atypical variants that were larger or smaller than the standard duplication classes used in our analyses. We documented the ascertainment criteria, country of origin, authors, and the demographic, clinical, and genotypic characteristics of subjects in different studies, and used these variables to attempt to identify duplicate cases reported in two or more papers.…”

“…Four studies were excluded because the sources of subjects overlapped with those of other reports and/or the origin of cases was not specified. 17,18,32,34 We compiled data for 107 subjects from the remaining 22 studies 1,2,[5][6][7][8][9][10][11][19][20][21][22][23][24][25][26][27][28][29][30]33 for the main analyses in this report.…”

Copy number variation in patients with cervical artery dissection

“…5 Rare copy number variants (CNVs) have a role in the etiology of tetralogy of Fallot, sporadic epilepsy syndromes or autism. [6][7][8] In patients with sporadic aortic aneurysms and dissections rare CNVs were identified that disrupt genes involved in vascular smooth muscle function. 9 The current study was the first analysis of CNVs in CeAD.…”