Journal Article

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Clur, Sally-Ann, Dutman, Annemiek C., Ta-Shma, Asaf, Hababa, Mariam, Tomek, Viktor, Denommé-Pichon, Anne-Sophie, de Knijff, Peter, Jacober, Jennifer, Ambrose, Matthew, Brown, H. Alex, Mustafa, Hiba, Lodder, Elisabeth M., Magliozzi, Monia, Moss, Timothy, Aristidou-Kallika, Aphrodite, Radio, Francesca Clementina, Lahrouchi, Najim, Santen, Gijs W.E., de Leeuw, Rick, Herkert, Johanna C., Burn, Sabrina C., Tanteles, George, van den Hoff, Maurice J.B., Ange-Line, Bruel, Ilgun, Aho, Haak, Monique C., Elpeleg, Orly, Postma, Alex V., Škorić-Milosavljević, Doris, Stránecký, Viktor, Frohman, Michael A., Robinson, Jamille Y., Niyazov, Dmitriy M., Bezzina, Connie R., Kmoch, Stanislav, Airola, Michael V., Piherová, Lenka, Harkel, Arend D. J. Ten, Mulder, Barbara, Barnett, Joey V., Salazar, Christian M., Tjong, Fleur, Manten, Gwendolyn T.R., Rousounides, Andreas, Ortiz, Damara, De Laughter, Daniel M., Cherny, Sara, Gunst, Quinn, Bowling, Forrest Z., Wolf, Barry, Kim, Katherine H., Bouman, Katelijne, Francannet, Christine, Zimmerman, Dominic, Beekman, Leander, Perles, Zeev

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Alleles / Biomedical research / Birth defects / Cardiomyopathy / Cardiovascular disease / Care and treatment / Congenital defects / Congenital diseases / Congenital heart disease / Coronary artery disease / Diagnosis / Enzymatic activity / Female / Gene expression / Gene frequency / Genetic aspects / Genetic variation / Haplotypes / Health aspects / Heart / Heart Defects, Congenital - enzymology / Heart Defects, Congenital - genetics / Heart diseases / Heart Valve Diseases - enzymology / Heart Valve Diseases - genetics / Humans / Jewish people / Loss of Function Mutation / Male / Mesenchyme / Neonates / Newborn babies / Parents & parenting / Patients / Phospholipase D - genetics / Phospholipase D - metabolism / Phospholipase D1 / Phospholipases / Principal components analysis / Proteins / Pulmonary arteries / Rheumatic heart disease / Signal transduction