Rajiv D. Machado, Carrie L. Welch, Matthias Haimel, Marta Bleda, Elizabeth Colglazier, John D. Coulson, Marusa Debeljak, Josef Ekstein, Jeffrey R. Fineman, William Christopher Golden, Emily L. Griffin, Charaka Hadinnapola, Michael A. Harris, Yoel Hirsch, Julie Elizabeth Hoover- Fong, Lawrence Nogee, Lewis H. Romer, Samo Vesel, NIHR Bioresource – Rare Diseases, Stefan Gräf, Nicholas W. Morrell, Laura Southgate, Wendy K. Chung
St George’s University of London. Columbia University Irving Medical Center. University of Cambridge. University of California San Francisco. Johns Hopkins University School of Medicine. University Medical Centre Ljubljana. Vici Syndrome Foundation. Teaching Hospital Celje.
United Kingdom, United States and Slovenia
Journal of Medical Genetics
J Med Genet 2022; 59: 906-911
DOI: 10.1136/jmedgenet-2021-107831
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.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access Free PDF File or Full Text Article Available Through PubMed or DOI: Yes