Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Abstract

Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9–107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4–22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100–200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8–64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus.

1q21.1 Microduplication expression in adults

“…Of the 31 relatives with 1q21.1 duplications, 26 were transmitting parents and five were siblings. The 76 probands (including adults and children) comprised 70 subjects ascertained because of major clinical features, five reported in nonoverlapping control populations, 2,5,6 and one parent of a child with autism spectrum disorder where the child did not have a 1q21.1 duplication. 22 The majority were referred from centers in Europe or the United States.…”

“…Soemedi et al 5 identified 1q21.1 duplications in 3 of 10,910 (0.027%) individuals originating from multiple source cohorts. Two were from the Wellcome Trust Case-Control Consortium 2 control cohort of 5,919 (0.034%) adults from the 1958 British Birth Cohort and the UK Blood Service (http://www.wtccc.org.…”

“…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.…”