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 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 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 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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Article numbere142148
JournalJournal of Clinical Investigation
Issue number5
StatePublished - Mar 1 2021

Bibliographical note

Funding Information:
We thank the families for their participation and collaboration. CRB, AVP and NL acknowledge the support from the Dutch Heart Foundation (CVON 2018-30 PREDICT2 and CVON2014-18 CONCOR-GENES to CRB), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610, to CRB), the Children’s Heart Foundation (to CRB), and the PROCEED project funded under the ERA PerMed Joint Translational Call Initiative (to CRB). NL acknowledges support from the CONCOR-GENES Young Talent Program. This work was supported by NIH grants R35GM128666 (to MVA), T32GM092714 (to FZB), R01GM084251 (to MAF), and U54092551 (to DMD, JYR, and JVB) and National Science Foundation (NSF) grant 1612689 (to CMS). SK, VS, and LP were supported by the Ministry of Health of the Czech Republic (NV19-07-00136) and by institutional programs of the Charles University in Prague (UNCE/MED/007, SVV2016/260148 and PROGRES-Q26/LF1). We thank The National Center for Medical Genomics (LM2018132) for instrumental and technical support with the sequencing analysis (to SK, VS, and LP). The authors thank Daoud Sie (Amsterdam UMC, Amsterdam, the Netherlands) for advice on analyses of PCGC WES data. A subset of the WES data was generated by the PCGC under the auspices of the NHLBI’s Bench to Bassinet Program ( (dbGaP study accession number phs001194.v2.p2). The PCGC program is funded by the National Heart, Lung, and Blood Institute (NHLBI), NIH, US Department of Health and Human Services, through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. This manuscript was not prepared in collaboration with investigators of the PCGC, has not been reviewed or approved by the PCGC, and does not necessarily reflect the opinions of the PCGC investigators or the NHLBI.

Publisher Copyright:
© 2021, American Society for Clinical Investigation.


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