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

Najim Lahrouchi, Alex V. Postma, Christian M. Salazar, Daniel M. De Laughter, Fleur Tjong, Lenka Piherova, Forrest Z. Bowling, Dominic Zimmerman, Elisabeth M. Lodder, Asaf Ta-Shma, Zeev Perles, Leander Beekman, Aho Ilgun, Quinn Gunst, Mariam Hababa, Doris Skoric-Milosavljevic, Viktor Stranecky, Viktor Tomek, Peter de Knijff, Rick de LeeuwJamille 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 Denomme-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

    OnderzoeksoutputAcademicpeer review

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    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.1668F 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.

    Originele taal-2English
    Aantal pagina's13
    TijdschriftCLIN Journal
    Nummer van het tijdschrift5
    StatusPublished - 1-mrt-2021

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