Abstract 2004: A Systematic CNV Screen in Left Ventricular Outflow Tract Obstruction
Purpose: Obstruction of the left ventricular outflow tract (LVOTO) contributes significantly to infant mortality and has serious implications in adult cardiology. The spectrum of LVOTO ranges from bicuspid aortic valve to hypoplastic left heart syndrome. Recently, small DNA changes of 1kb to several megabases (named copy number variants, CNVs) have been recognized as a source of variation in the human genome. We hypothesized that structural genomic variants contribute causally to LVOTO.
Methods: We accessed a provincial biobank, from which 43 families with at least one member with LVOTO were ascertained. All participants gave informed consent and underwent physical exam, ECG and echocardiography. Genotyping was performed on the Affymetrix 6.0 platform. We used Genotyping Console 3.0.2 at settings of different sensitivity for in silico detection of CNVs. 112 severely affected patients were compared to 139 healthy individuals and 115 HapMap Controls. Thresholds were set at a minimum of 10 consecutive marker deleted over 100 kb. WEBGESTALT was used to dissect significantly enriched genetic pathways, tissue distribution and cellular localization.
Results: Our analysis revealed a total of 2352 CNVs in 112 affecteds (21 CNVs per sample) versus 2612 CNVs in 139 unaffected individuals (19.8 per sample). In affecteds, 194 novel CNVs overlapping 149 different genes were identified (1.73 per sample), versus 194 CNVs overlapping 138 genes in unaffected (1.5 per sample). Most CNVs were private. Genes identified in affecteds showed a higher prevalence in muscle, embryonic and heart tissue. GTPase regulator activity was identified as a significantly enriched pathway. Other biologically plausible candidate genes and pathways include the WNT cascade (FUT8), angiogenesis (ANPTL3) and chromosomal maintenance.
Conclusions: The high prevalence of private CNVs is suggestive of genetically heterogeneous determinants contributing to LVOTO. Interestingly, GTPase regulator activity and chromosomal maintenance emerge as novel candidate pathways in human LVOTO. Further evaluation including cloning of breakpoints, replication studies and functional assays is warranted and will permit genotype-phenotype correlation.