Clinical implications of large rare copy number variations in 110 Chinese patients with conotruncal heart disease

Abstract

Background and aims Conotruncal heart anomalies, or defects affecting the cardiac outflow tract, contributes to a significant proportion (42.7%) of paediatric structural congenital heart diseases (CHD) in Hong Kong. Recent studies of copy number variations (CNV) in Tetralogy of Fallot (TOF) suggest that structural variations in the genome may be an important genetic cause of the disease. Our objective is to look at large (>500kb), rare (<1% in controls) CNVs in this disease group, searching for pathogenic variants, using a rare disease, rare variant hypothesis. Methods Adults with conotruncal heart anomalies (n=213) were recruited from the adult CHD clinic, and 22q11.2 deletion syndromes were excluded (n=24, 11%). After qPCR, 118 out of 189 individuals were consented, and DNA samples were sent for Affymetrix 6.0 genome-wide array analysis. Using a stringent calling criteria, high confident calls were obtained from 110 samples. A large control set consisting of 5902 Caucasian and Singapore subjects was used to identify rare changes, and the large CNVs selected for validation on a different array platform. Results Ten patients (9%) were found to have large rare CNVs, and were called back for assessment, of which 3 were found to be syndromic. Interestingly, CNVs of syndromic patients also overlapped regions of potential interest. First is a 611kb deletion at 17p13. 3 telomeric to the Miller-Dieker syndrome (MDS) region, overlapping the NXN gene. The second CNV is a large duplication at 2q22.3 overlapping the ZEB2 gene. Two other CNVs were found in the 13q31.2-qter region, a 5Mb deletion and a 1.5Mb copy gain. Literature on 13q terminal deletion suggests that 13q31.1-34 is a critical region for CHD, including TOF, which is further supported by two Chinese reports of deletions in 13q33-34.

Conclusion We found a similar yield of large rare CNVs compared to studies of TOF in Caucasian subjects, a size detectable by clinical arrays. The pattern of distribution appears to be different in the Chinese population, but the finding suggests that CNVs may contribute to a significant proportion of CHD, comparable to that of point mutations (10%). Acknowledgements SK Yee Medical Research Foundation and Hong Kong Children's Heart Foundation