biostudies-literatureMachado RDNIHRBritish Heart FoundationNIHR Cambridge Biomedical Research CentreNHS Blood and TransplantNHSNational Institute for Health Research (NIHR)Special Project Grant and Personal Chair Award to NWMWellcome TrustAcademy of Medical SciencesNHS Trusts906-911https://www.ebi.ac.uk/biostudies/studies/S-EPMC9411922biostudies-literatureUnknown59(9)<h4>Background</h4>The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the <i>ATP13A3</i> gene were recently identified as a new cause of adult-onset PAH. However, the contribution of <i>ATP13A3</i> risk alleles to child-onset PAH remains largely unexplored.<h4>Methods and results</h4>We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic <i>ATP13A3</i> variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disJournal of medical geneticsBiallelic variants of <i>ATP13A3</i> cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.PMC9411922204809/Z/16/ZSBF005\1115BRC-1215-20014Debeljak MBleda MSouthgate LEkstein JHoover-Fong JEMachado RDGolden WCRomer LHNIHR Bioresource – Rare DiseasesMorrell NWHadinnapola CVesel SHarris MAFineman JRHirsch YWelch CLCoulson JDChung WKColglazier EGriffin ELNogee LHaimel MGraf SfalseBiallelic variants of <i>ATP13A3</i> cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.<h4>Background</h4>The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the <i>ATP13A3</i> gene were recently identified as a new cause of adult-onset PAH. However, the contribution of <i>ATP13A3</i> risk alleles to child-onset PAH remains largely unexplored.<h4>Methods and results</h4>We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic <i>ATP13A3</i> variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with dis2022-01-01T00:00:00Z2022 Sep2025-05-29T16:11:37.81Z2025-04-04T09:32:19.981ZS-EPMC94119223449354410.1136/jmedgenet-2021-107831