Biallelic variants of <i>ATP13A3</i> cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality
Rajiv D. Machado, Carrie L. Welch, Matthias Haimel, Marta Bleda, Elizabeth Colglazier, John D. Coulson, Maruša Debeljak, Josef Ekstein, Jeffrey R. Fineman, W. Christopher Golden, Emily L. Griffin, Charaka Hadinnapola, Michael A. Harris, Yoel Hirsch, Julie Hoover‐Fong, Lawrence M. Nogee, Lewis H. Romer, Samo Vesel, NIHR Bioresource – Rare Diseases, Stefan Gräf, Nicholas W. Morrell, Laura Southgate, Wendy K. Chung
Abstract
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.