Abstract
Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.
Highlights
Left-ventricular outflow tract obstructions (LVOTO) comprise a group of cardiac malformations that restrict blood flow in the left portion of the heart
Left-ventricular outflow tract obstructions comprise a group of developmental heart disorders that are genetically and phenotypically heterogeneous, with no single gene accounting for the majority of cases
A recent study has suggested that NOTCH1 haploinsufficiency alters specific gene networks affecting valve development and osteogenic factors which in turn result in aortic valve disease [16]
Summary
Left-ventricular outflow tract obstructions (LVOTO) comprise a group of cardiac malformations that restrict blood flow in the left portion of the heart This heterogeneous subclass of cardiac malformations is commonly associated with aortic valve disease and early onset aortopathy, including severe stenosis and aortic dilation. Recent studies suggest that multiple genes in conserved signaling pathways mediating important cues for crucial processes during early embryonic development contribute to disease. Both familial and sporadic occurrences of LVOTO have been associated with mutations in genes of the Notch-signaling cascade [11,12]. A recent study has suggested that NOTCH1 haploinsufficiency alters specific gene networks affecting valve development and osteogenic factors which in turn result in aortic valve disease [16]. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlation
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