Objectives With more patients with congenital heart disease (CHD) surviving to childbearing age, it becomes even more critical to understand the genetic origins of CHD. Chromosomal imbalances have been identified in many forms of syndromic CHD, but the impact of copy number variation in isolated CHD is still largely uncovered. We hypothesised that adult cases with isolated CHD have novel chromosomal abnormalities, which might identify new disease-related loci or genes for various cardiac defects. We provide here the submicroscopic imbalances of isolated adult CHD (ACHD). We hypothesised that isolated adult cases CHD have specific spectrum of chromosomal imbalance, which might help identify new disease-related loci or genes for various cardiac defects.
Methods In order to identify new genetic causes in patients of CHD, A total of 103 adults with diverse range of isolated CHD and 50 ethnically matched controls were prospectively screened using whole-genome array comparative genomic hybridisation (array-CGH).
Results 18 large (>100kb) novel copy number abnormalities that neither correspond to DNA copy number changes as listed in the Database of Genomic Variants, nor could be found in 50 controls were identified in 103 patients (48.5%): 7 deletions and 11 duplications. In 2 genomic imbalances (18q23, 3q21.2), genes known to be associated with heart development were implicated (NFATC1, PLXNA1). Known recurrent CNV was identified at 22q11.2 in one case without any extracardiac manifestation. In addition, one inherited aberrations unreported thus far were detected, the causal relationship with CHD remains to be established.
Conclusions This study identifies a known disease locus (22q11.2) and highlights additional CNVs (e.g., 18q23, 3q21.2) for further investigation. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in adults with isolated CHD. Besides their usefulness in genetic counseling, identified genomic imbalances may aid in the medical follow-up of these individuals.