RT Journal Article SR Electronic T1 Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 906 OP 911 DO 10.1136/jmedgenet-2021-107831 VO 59 IS 9 A1 Rajiv D Machado A1 Carrie L Welch A1 Matthias Haimel A1 Marta Bleda A1 Elizabeth Colglazier A1 John D Coulson A1 Marusa Debeljak A1 Josef Ekstein A1 Jeffrey R Fineman A1 William Christopher Golden A1 Emily L Griffin A1 Charaka Hadinnapola A1 Michael A Harris A1 Yoel Hirsch A1 Julie Elizabeth Hoover-Fong A1 Lawrence Nogee A1 Lewis H Romer A1 Samo Vesel A1 NIHR Bioresource – Rare Diseases A1 Stefan Gräf A1 Nicholas W Morrell A1 Laura Southgate A1 Wendy K Chung YR 2022 UL http://jmg.bmj.com/content/59/9/906.abstract AB Background 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 ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored.Methods and results We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 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 disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic.Conclusion Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.