Abstract
Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
Highlights
Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies, with a worldwide occurrence of 7 per 1000 live births [1]
We searched for additional patients carrying biallelic variants in phospholipase D1 (PLD1) by performing (a) whole-exome sequencing (WES) for 75 patients with similar severe right-sided congenital heart defects from the National Registry of Congenital Heart Defects (CONCOR) in the Netherlands [7]; (b) analysis of 2643 patients with congenital heart disease trios who underwent WES from the Pediatric Cardiac Genomics Consortium (PCGC) [8, 9]; and (c) a search using GeneMatcher [4]
While this is in line with the previous report on 2 families with individuals who had PLD1-related autosomal-recessive congenital heart disease [3], in this study, we identified 5 patients with autosomal-recessive variants in PLD1 who were diagnosed with Ebstein’s anomaly
Summary
Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies, with a worldwide occurrence of 7 per 1000 live births [1]. The majority of these defects include abnormalities of valve formation. Right-sided congenital heart disease includes abnormalities of the pulmonary and tricuspid valves, the right ventricle, and the right ventricular outflow tract. No overt structural cardiac defects were noted, mice lacking PLD1 displayed moderately impaired function of the pulmonary and tricuspid valve on echocardiography [3]. The functional consequences of PLD1 enzymatic activity and the mechanism by which PLD1 dysfunction leads to congenital valve abnormalities remain unknown
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