Table 1.

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

Case	Sex	Age at diagnosis	Age at death	mPAP (mm Hg)	PVRi (Woods units)	Treatment	Variant(s)	Mutation type	MAF gnomAD v2.1.1 (controls)	CADD score h38v1.6	SIFT	PolyPhen2 (HumVar)	Previously-reported for PAH?	ACMG class
F1 II.1	M	2.5 years	4 years	nk		Sildenafil and diuretics	c.2563G>A (p.Val855Met) rs1489314131	Missense (homozygous)	absent	26.5	D	D	Barozzi 201914	LP
F1 II.2	M	2.5 years	8 years	40		Sildenafil, bosentan, intravenous epoprostenol and lung transplantation	c.2563G>A (p.Val855Met) rs1489314131	Missense (homozygous)	absent	26.5	D	D	Barozzi 201914	LP
F2 II.2	M	5 months	11 months	34*	11.8	Oxygen, diuretics, sildenafil, bosentan and intravenous treprostinil	c.2549dupT (p.Met850Ilefs13) rs1560082927	Frameshift	9.21e-6 (no homo)	33	D	D	Zhu 20194	P
							c.2227C>T (p.Arg743Cys)	Missense	absent	32	D	D	Zhu 20194	LP
F2 II.4	F	7 days	17 months	51*	11.8	Oxygen, diuretics, sildenafil, bosentan and subcutaneous treprostinil	c.2549dupT (p.Met850Ilefs13) rs1560082927	Frameshift	9.21e-6 (no homo)	33	D	D	Zhu 20194	P
							c.2227C>T (p.Arg743Cys)	Missense	absent	32	D	D	Zhu 20194	LP
F3 I.1	F	22 months	alive	59*	34.3	Sildenafil, bosentan, treprostinil and digoxin	c.3079dupT (p.Trp1027Leufs9) rs746602775	Frameshift	absent	absent	---	--	no	P
							c.3685G>T (p.Glu1229) rs200914446	Nonsense	absent	26.4	---	---	no	P

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.