Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy
Najim Lahrouchi, … , Michael A. Frohman, Connie R. Bezzina
Najim Lahrouchi, … , Michael A. Frohman, Connie R. Bezzina
Published March 1, 2021
Citation Information: J Clin Invest. 2021;131(5):e142148. https://doi.org/10.1172/JCI142148.
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Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

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.

Authors

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

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Figure 1

Recessive variants in PLD1 cause a spectrum of valvular congenital heart disease and neonatal cardiomyopathy.

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Recessive variants in PLD1 cause a spectrum of valvular congenital heart...
(A) Pedigrees. Solid symbols indicate the affected individuals (black indicates individuals with a congenital heart defect; red indicates individuals with fetal/neonatal cardiomyopathy), and symbols with a slash through them indicate deceased individuals. A double line indicates consanguinity. Males are indicated by squares and females by circles. Solid black triangles with a slash through them indicate fetal death or termination of pregnancy. Gray triangles indicate a miscarriage. Dup, duplication; ex, exon; fs, frame shift; NA, not available; Ter, termination; wk, age in weeks at termination of the pregnancy. #Previously published family (3). Families H–M were identified through analysis of PCGC data, and pedigrees were not available (8, 9). (B) PLD1 domain structure and location of pathologic (bottom) and presumptive nonpathologic (top) missense variants. Black indicates an inactive allele (16) used as a baseline control. Gray dots, homozygous missense variants found in gnomAD individuals (11). Statistical comparison of loop variants in patients versus controls was performed using Fisher’s exact test (P = 0.017). (C) Macroscopic appearance of the heart of fetus II-5 from family A. Upper left panel: Position of the heart in the thorax. Note the extremely dilated right ventricle with a thin translucent wall. A sharp demarcation can be seen between the abnormal right ventricular myocardium and normal left ventricular myocardium. Upper right panel: Anterior view of a formalin-fixed heart including large vessels, showing the paper-thin right ventricular wall, which was partially collapsed because of tissue weakness. Bottom panels: Postnatal echocardiograms of child II-1 from family A displaying a thin-walled right ventricle with Ebstein’s anomaly of the tricuspid valve and tricuspid regurgitation (see also Supplemental Video 1). This child also had pulmonary atresia. Ao, ascending aorta; Diaph, thoracic diaphragm; LA, left atrium; LAA, left atrial appendage; LV, left ventricle; PT, pulmonary trunk; RAA, right atrial appendage; RV, right ventricle; TV, tricuspid valve; TR, tricuspid regurgitation.