Dataset Information

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.

SUBMITTER: Lahrouchi N

PROVIDER: S-EPMC7919725 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Lahrouchi Najim N Postma Alex V AV Salazar Christian M CM De Laughter Daniel M DM Tjong Fleur F Piherová Lenka L Bowling Forrest Z FZ Zimmerman Dominic D Lodder Elisabeth M EM Ta-Shma Asaf A Perles Zeev Z Beekman Leander L Ilgun Aho A Gunst Quinn Q Hababa Mariam M Škorić-Milosavljević Doris D Stránecký Viktor V Tomek Viktor V de Knijff Peter P de Leeuw Rick R Robinson Jamille Y JY Burn Sabrina C SC Mustafa Hiba H Ambrose Matthew M Moss Timothy T Jacober Jennifer J Niyazov Dmitriy M DM Wolf Barry B Kim Katherine H KH Cherny Sara S Rousounides Andreas A Aristidou-Kallika Aphrodite A Tanteles George G Ange-Line Bruel B Denommé-Pichon Anne-Sophie AS Francannet Christine C Ortiz Damara D Haak Monique C MC Ten Harkel Arend D.J. AD Manten Gwendolyn Tr GT Dutman Annemiek C AC Bouman Katelijne K Magliozzi Monia M Radio Francesca Clementina FC Santen Gijs We GW Herkert Johanna C JC Brown H Alex HA Elpeleg Orly O van den Hoff Maurice Jb MJ Mulder Barbara B Airola Michael V MV Kmoch Stanislav S Barnett Joey V JV Clur Sally-Ann SA Frohman Michael A MA Bezzina Connie R CR

The Journal of clinical investigation 20210301 5

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. F ...[more]

PMID: 33645542

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Project description:BackgroundCongenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database.ResultsWe discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327.ConclusionsOur results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Dataset Information

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

Publications

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

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