Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3213006

Documents

In Collections

This item can be found in the following collections:

Lahrouchi, N.; Postma, A.V.; Salazar, C.M.; Laughter, D.M. de; Tjong, F.; Piherova, L.; ... ; Bezzina, C.R. (2021)

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

Article / Letter to editor
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...Show moreCongenital 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.Show less
All authors
Lahrouchi, N.; Postma, A.V.; Salazar, C.M.; Laughter, D.M. de; Tjong, F.; Piherova, L.; Bowling, F.Z.; Zimmerman, D.; Lodder, E.M.; Ta-Shma, A.; Perles, Z.; Beekman, L.; Ilgun, A.; Gunst, Q.; Hababa, M.; Skoric-Milosavljevic, D.; Stranecky, V.; Tomek, V.; Knijff, P. de; Leeuw, R. de; Robinson, J.Y.; Burn, S.C.; Mustafa, H.; Ambrose, M.; Moss, T.; Jacober, J.; Niyazov, D.M.; Wolf, B.; Kim, K.H.; Cherny, S.; Rousounides, A.; Aristidou-Kallika, A.; Tanteles, G.; Ange-Line, B.; Denomme-Pichon, A.S.; Francannet, C.; Ortiz, D.; Haak, M.C.; Harkel, A.D.J. ten; Manten, G.T.R.; Dutman, A.C.; Bouman, K.; Magliozzi, M.; Radio, F.C.; Santen, G.W.E.; Herkert, J.C.; Brown, H.A.; Elpeleg, O.; Hoff, M.J.B. van den; Mulder, B.; Airola, M.V.; Kmoch, S.; Barnett, J.V.; Clur, S.A.; Frohman, M.A.; Bezzina, C.R.
Date
2021-03-01
Journal
Journal of Clinical Investigation
Volume
131
Issue
5
DOI
doi:10.1172/JCI142148
Link
http://www.jci.org/articles/view/142148/files/pdf