Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events

Abstract

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.

Keywords: aortic stenosis; chromosome; coarctation aorta; congenital heart disease; genetic; hypoplastic left heart syndrome.

Figure 1

Large CNVs on chromosome 11q24-q25 detected by SNP microarray. Figure shows the logR Ratio (LRR) and B-allele frequency (BAF) of SNPs genotyped across chromosome 11 in three LSL probands. Loss of single copy number is shaded in orange; gain of a single copy is shaded in purple.

Figure 2

CNV loci in CHD patients. The overlap of large CNV events observed in this study (light blue circles, blue lines, dark blue shading) with large (1–10 mb) CNV regions reported in more than five CHD cases by Thorsson et. al.³⁶ (dark blue circles, red lines, red shading).

Figure 3

Cardiac development candidate genes (yellow labels) inferred from ‘unique’ large CNV regions identified. Inferred cardiac development genes and corresponding network are shown in grey shading.