Table 1

Clinical phenotypes and ATP13A3 variants identified in childhood-onset, autosomal recessive PAH

CaseSexAge at diagnosisAge at deathmPAP (mm Hg)PVRi (Woods units)TreatmentVariant(s)Mutation typeMAF gnomAD v2.1.1 (controls)CADD score h38v1.6SIFTPolyPhen2 (HumVar)Previously-reported for PAH?ACMG class
F1 II.1M2.5 years4 yearsnkSildenafil and diureticsc.2563G>A (p.Val855Met)
Missense (homozygous)absent26.5DDBarozzi 201914LP
F1 II.2M2.5 years8 years40Sildenafil, bosentan, intravenous epoprostenol and lung transplantationc.2563G>A (p.Val855Met)
 Missense (homozygous)absent26.5DD Barozzi 201914 LP
F2 II.2M5 months11 months34*11.8Oxygen, diuretics, sildenafil, bosentan and intravenous treprostinilc.2549dupT (p.Met850Ilefs13) rs1560082927Frameshift9.21e-6 (no homo)33DDZhu 20194P
c.2227C>T (p.Arg743Cys)Missenseabsent32DDZhu 20194LP
F2 II.4F7 days17 months51*11.8Oxygen, diuretics, sildenafil, bosentan and subcutaneous treprostinilc.2549dupT (p.Met850Ilefs13) rs1560082927Frameshift9.21e-6 (no homo)33DDZhu 20194P
c.2227C>T (p.Arg743Cys)Missenseabsent32DDZhu 20194LP
F3 I.1F22 monthsalive59*34.3Sildenafil, bosentan, treprostinil and digoxinc.3079dupT (p.Trp1027Leufs9) rs746602775Frameshiftabsentabsent-----noP
c.3685G>T (p.Glu1229) rs200914446Nonsenseabsent26.4------noP
  • Variant nomenclature according to transcript NM_001367549.1.

  • Deleteriousness predictions: CADD score>20: deleterious; SIFT or PolyPhen score=D: protein damaging.

  • ACMG class: LP: likely pathogenic; P: pathogenic.

  • *Non-responder to inhaled nitric oxide or oxygen. F1 II.1 and II.2 were not tested.

  • CADD, Combined Annotation Dependent Depletion; mPAP, mean pulmonary artery pressure; nk, not known; PAH, pulmonary arterial hypertension; PVRi, pulmonary vascular resistance index; SIFT, Sorting Intolerant from Tolerant.