PT  - JOURNAL ARTICLE
AU  - Rajiv D Machado
AU  - Carrie L Welch
AU  - Matthias Haimel
AU  - Marta Bleda
AU  - Elizabeth Colglazier
AU  - John D Coulson
AU  - Marusa Debeljak
AU  - Josef Ekstein
AU  - Jeffrey R Fineman
AU  - William Christopher Golden
AU  - Emily L Griffin
AU  - Charaka Hadinnapola
AU  - Michael A Harris
AU  - Yoel Hirsch
AU  - Julie Elizabeth Hoover-Fong
AU  - Lawrence Nogee
AU  - Lewis H Romer
AU  - Samo Vesel
AU  - NIHR Bioresource – Rare Diseases
AU  - Stefan Gräf
AU  - Nicholas W Morrell
AU  - Laura Southgate
AU  - Wendy K Chung
TI  - Biallelic variants of <em>ATP13A3</em> cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality
AID  - 10.1136/jmedgenet-2021-107831
DP  - 2022 Sep 01
TA  - Journal of Medical Genetics
PG  - 906--911
VI  - 59
IP  - 9
4099  - http://jmg.bmj.com/content/59/9/906.short
4100  - http://jmg.bmj.com/content/59/9/906.full
SO  - J Med Genet2022 Sep 01; 59
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.