ArticleThe Journal of clinical investigation2021
Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
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Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- A case report of right ventricular cardiomyopathy with right ventricular diverticulum and atrial septal defect associated with biallelic PLD1 gene variants.European heart journal. Case reports · 2026Article
- Novel compound heterozygous variants in theFrontiers in cardiovascular medicine · 2026Article
- Recessive genetic contribution to congenital heart disease in 5,424 probands.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Phospholipase D1 is a critical mediator of neutrophil extracellular trap formation and venous thrombosis.Frontiers in immunology · 2025Article
- Genetic etiology and pregnancy outcomes of abnormal fluid accumulation in fetus: A retrospective cohort study.PloS one · 2025Article
- Genetic and Environmental Contributors To Congenital Heart Disease.Current treatment options in cardiovascular medicine · 2025Review
- Simultaneous CNV-seq and WES: An effective strategy for molecular diagnosis of unexplained fetal structural anomalies.Heliyon · 2024Article
- SomaticExperimental and therapeutic medicine · 2024Article
- Human Genetics of Ventricular Septal Defect.Advances in experimental medicine and biology · 2024Article
- Prenatal detection of novel compound heterozygous variants of theFrontiers in genetics · 2024Article
- Discovery ofAmerican journal of translational research · 2024Article
- Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report.Journal of medical case reports · 2023Article
- Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy.European journal of human genetics : EJHG · 2023Article
- Discovery ofBiology · 2023Article
- Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.Pharmacogenomics and personalized medicine · 2023Article
- Defining the proximal interaction networks of Arf GTPases reveals a mechanism for the regulation of PLD1 and PI4KB.The EMBO journal · 2022Article
- Identification ofDiagnostics (Basel, Switzerland) · 2022Article
- A novelExperimental and therapeutic medicine · 2022Article
- Structure and regulation of human phospholipase D.Advances in biological regulation · 2021Review
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Authors and funding
56 authors at 20 institutions in 8 countries.
Najim LahrouchiAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Alex V PostmaDepartment of Clinical Genetics, and.
Christian M SalazarDepartment of Pharmacological Sciences and Graduate Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York, USA.
Daniel M De LaughterDepartment of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Fleur TjongAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Lenka PiherováResearch Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
Forrest Z BowlingDepartment of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
Dominic ZimmermanAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Elisabeth M LodderAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Asaf Ta-ShmaDepartment of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Zeev PerlesDepartment of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Leander BeekmanAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Aho IlgunDepartment of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands.
Quinn GunstDepartment of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands.
Mariam HababaAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Doris Škorić-MilosavljevićAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Viktor StráneckýResearch Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
Viktor TomekChildren's Heart Centre, 2nd Faculty of Medicine, Charles University in Prague, Motol University Hospital, Prague, Czech Republic.
Peter de KnijffDepartment of Human Genetics, Leiden University Medical Centre, Leiden, Netherlands.
Rick de LeeuwDepartment of Human Genetics, Leiden University Medical Centre, Leiden, Netherlands.
Jamille Y RobinsonDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Sabrina C BurnDepartment of Obstetrics, Gynecology and Women's Health.
Hiba MustafaDepartment of Obstetrics, Gynecology and Women's Health.
Matthew AmbroseDepartment of Pediatrics, Division of Pediatric Cardiology, and.
Timothy MossDepartment of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
Jennifer JacoberDepartment of Pediatrics, Ochsner Clinic, Tulane University, University of Queensland, New Orleans, Louisiana, USA.
Dmitriy M NiyazovDepartment of Pediatrics, Ochsner Clinic, Tulane University, University of Queensland, New Orleans, Louisiana, USA.
Barry WolfDivision of Genetics, Birth Defects and Metabolic Disorders, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Katherine H KimDivision of Genetics, Birth Defects and Metabolic Disorders, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Sara ChernyFeinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Andreas RousounidesMakarios Medical Centre, Nicosia, Cyprus.
Aphrodite Aristidou-KallikaUltrasound and Fetal Medicine Diagnostic Centre, Nicosia, Cyprus.
George TantelesCyprus School of Molecular Medicine, Nicosia, Cyprus.
Bruel Ange-LineUMR 1231 INSERM, GAD, Université Bourgogne Franche-Comté, Dijon, France.
Anne-Sophie Denommé-PichonUMR 1231 INSERM, GAD, Université Bourgogne Franche-Comté, Dijon, France.
Christine FrancannetService de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
Damara OrtizMedical Genetics Department, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Monique C HaakDepartment of Obstetrics and.
Arend D.J. Ten HarkelDepartment of Pediatric Cardiology, Leiden University Medical Centre, Leiden, Netherlands.
Gwendolyn Tr MantenDepartment of Obstetrics and.
Annemiek C DutmanDepartment of Pathology, Isala Women and Children's Hospital, Zwolle, Netherlands.
Katelijne BoumanUniversity Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, Netherlands.
Monia MagliozziGenetic and Rare Disease Research Division, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Francesca Clementina RadioGenetic and Rare Disease Research Division, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.
Gijs We SantenDepartment of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Johanna C HerkertUniversity Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, Netherlands.
H Alex BrownDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Orly ElpelegDepartment of Genetics, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Maurice Jb van den HoffDepartment of Medical Biology, Amsterdam UMC, Amsterdam, Netherlands.
Barbara MulderAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Michael V AirolaDepartment of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
Stanislav KmochResearch Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
Joey V BarnettDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Sally-Ann ClurDepartment of Pediatric Cardiology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Michael A FrohmanDepartment of Pharmacological Sciences and Graduate Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York, USA.
Connie R BezzinaAmsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.
Amsterdam Neuroscience · NLCharles University · CZStony Brook University · USVanderbilt University · USAmsterdam University Medical Centers · NLHadassah Medical Center · ILNorthwestern University · USBambino Gesù Children's Hospital · ITInserm · FRLeiden University · NLLeiden University Medical Center · NLPediatrics and Genetics · USTulane University · USUniversity Medical Center Groningen · NLWomen's Health Research Institute · CACentre Hospitalier Universitaire de Clermont-Ferrand · FRChildren's Hospital of Pittsburgh · USCyprus Institute of Neurology and Genetics · CYEmma Kinderziekenhuis · NLIsala · NL
Funding
Administrative Coordinating Center: Cardiovascular Development and Pediatric Cardiac Genomics ConsortiaU01HL131003 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI CNOTA, JAMES, OLLBERDING, NICHOLAS J · 2016 to 2024
$54.8MStructure and regulation of lipid metabolism and transportR35GM128666 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI Michael Virgil Airola · 2018 to 2026
$4.0MLipid-signaling pathways regulating mitochondrial morphology, energetics, and movR01GM084251 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI FROHMAN, MICHAEL A. · 2009 to 2017
$2.6MGenetics of Hypoplastic Left Heart SyndromeUM1HL128761 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI BERNSTEIN, DANIEL, SRIVASTAVA, DEEPAK · 2015 to 2019
$2.5MThe Genomic Basis of Congenital Heart Disease and Neurodevelopmental OutcomesUM1HL098147 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI NEWBURGER, JANE W., ROBERTS, AMY E · 2015 to 2019
$2.4MGenetics of conotruncal defects and associated neurodevelopmental outcomesUM1HL098123 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GELB, BRUCE D · 2015 to 2019
$2.3MGenetics and genomics of congenital heart disease and associated neurodevelopmental abnormalitiesUM1HL098162 · NHLBI · YALE UNIVERSITY · PI BRUECKNER, MARTINA, GUPTA, ABHA RANI · 2015 to 2019
$2.2MBridging the Gap between Genomics and Clinical Outcomes in CHDUM1HL128711 · NHLBI · UNIVERSITY OF UTAH · PI TRISTANI-FIROUZI, MARTIN, YANDELL, MARK DOUGLAS · 2015 to 2019
$2.0MSBU Chemistry-Biology Interface Training ProgramT32GM092714 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI SAMPSON, NICOLE S, TONGE, PETER J · 2010 to 2019
$1.7MPediatric Heart Network Joint Heart Program ConsortiumUM1HL172717 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI Louis Bezold, James Cnota · 2024 to 2026
$1.3MNHLBI NIH HHS U01 HL131003NHLBI NIH HHS UM1 HL098123NHLBI NIH HHS UM1 HL098147NHLBI NIH HHS UM1 HL098162NHLBI NIH HHS UM1 HL128711NHLBI NIH HHS UM1 HL128761NHLBI NIH HHS UM1 HL172717NIGMS NIH HHS R01 GM084251NIGMS NIH HHS R35 GM128666NIGMS NIH HHS T32 GM092714
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.
Indexed as
AllelesHeart Defects, CongenitalHeart Valve DiseasesLoss of Function MutationPhospholipase DFemaleHumansMalePhospholipase Dphospholipase D1CardiologyCardiovascular diseaseGenetic diseasesGeneticsHeart failure
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.