Table 1.
Strength of PAH-gene relationships for genes implicated in isolated H/IPAH.
| Gene | Gene name | MOIa | Genetic evidence | Variant type scoreb | Experimental evidence | Evidence type scoredc | Total score | >3 yrs? | Classification | Tissue/cell expressiond | Molecular mechanisme |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ATP13A3 | ATPase 13A3 | AD/AR | 12 | pLOF | 1 | F/expression; FA/non-patient | 13 | Y 2018 | Definitive | PASMC, PAEC, BOEC | Unknown |
| BMPR2 | Bone morphogenetic protein receptor 2 | AD | 12 | pLOF | 6 | F/expression, biochemical, interaction; FA/patient; M/non-human; R/non-human | 18 | Y 2000 | Definitive | PASMC, PAEC | Haploinsufficiency |
| CAV1 | Caveolin 1 | AD | 6 | pLOF, missense | 6 | F/biochemical; FA/patient; M/non-human; R/non-human | Y 2012 | Definitive | Lung EC | Dominant negative | |
| GDF2 | Growth differentiation factor 2 | AD | 12 | pLOF, missense | 6 | F/expression, biochemical, interaction; FA/patient, non-patient; M/cell culture | 18 | Y 2016 | Definitive | HMVEC/PAEC | Haploinsufficiency |
| KCNK3 | Potassium two pore domain channel subfamily K member 3 | AD | 7 | missense | F/expression; FA/patient; M/non-human | 12 | Y 2013 | Definitive | Lung, PA, PASMC | LOF | |
| KDR | Kinase insert domain receptor | AD | 6.5 | 6 | F/expression; M/non-human | 12.5 | Y 2018 | Definitive | PAEC | Haploinsufficiency | |
| SMAD9 | Smad family member 9 | AD | 9.6 | pLOF, missense | 4.5 | F/biochemical, interaction; FA/patient, non-patient; R/patient cells | 14.1 | Y 2009 | Definitive | PAEC, PASMC | LOF |
| SOX17 | SRY-box transcription factor 17 | AD | 11.8 | pLOF, missense | 1.5 | F/expression; FA/non-patient | 13.3 | Y 2018 | Definitive | PAEC, PAH plexiform lesions | Haploinsufficiency |
| ABCC8 | ATP binding cassette subfamily C member 8 | AD | 9.0 | pLOF, missense | 1.0 | F/expression | 10 | Y 2018 | Moderate | Lung, PA | LOF |
| GGCX | Gamma glutamyl carboxylase | AD | 8.8 | pLOF, missense | 0.5 | F/expression | 9.3 | Y 2019 | Moderate | Lung | Unknown |
| TET2 | Tet-methylcytosine-dioxygenase-2 | AD | 4.6 | pLOF, missense | 3.5 | F/expression, biochemical; M/non-human | 8.1 | N 2020 | Moderate | Lung | LOF |
| AQP1 | Aquaporin 1 | AD | 3.3 | missense | 0.5 | F/expression | 3.8 | Y 2018 | Limited | PASMC, PAEC, BOEC | N/A |
| BMP10 | Bone morphogenetic protein 10 | AD | 1.9 | pLOF, missense | 1.1 | F/expression, biochemical, interaction | 3.0 | Y 2019 | Limited | Plasma, right atrium | Haploinsufficiency |
| FBLN2 | Fibulin 2 | AD | 2.0 | missense | 0.5 | F/expression | 2.5 | N 2021 | Limited | Heart, aorta coronaries; basement membrane | Unknown (GOF?) |
| KLF2 | Krüppel-like factor 2 | AD | 0.5 | missense | 3.0 | F/expression, interaction; FA/patient | Y 2017 | Limited | Lung, vasculature | N/A | |
| KLK1 | Tissue Kallikrein | AD | 5.2 | pLOF, missense | 0.5 | F/expression | 5.7 | Y 2019 | Limited | Lung, vasculature | Unknown (haploinsufficiency and/or LOF?) |
| PDGFD | Platelet Derived Growth Factor D | AD | 2.1 | 2.0 case-CTL data + 0.1 missense | 0.5 | 2.6 | N 2021 | Limited | Lung, vasculature, mesenchyme | Unknown (GOF?) | |
| TOPBP1 | DNA topoisomerase II binding protein 1 | N/A | 0 | none | 1.0 | F/expression; FA/non-patient | 1.0 | N/A | No known disease relationship | Lung, PAEC | N/A |
| BMPR1A | Bone morphogenetic protein receptor 1A | N/A | 0 | missense | F/expression, biochemical, interaction | 2.0 | Y 2018 | Disputed | PASMC | N/A | |
| BMPR1B | Bone morphogenetic protein receptor 1B | N/A | 0 | 2 | F/expression, biochemical, interaction | 2.0 | Y 2012 | Disputed | PASMC | N/A | |
| NOTCH3 | Notch receptor 3 | N/A | 0 | missense | 2.0 | F/expression, biochemical; FA/non-patient | 2.0 | Y 2014 | Disputed | Lung, PASMC | N/A |
| SMAD1 | Smad family member 1 | N/A | 0 | missense | 3.0 | F/biochemical; M/non-human | 3.0 | Y 2011 | Disputed | PAEC, PASMC | N/A |
| SMAD4 | Smad family member 4 | N/A | 0 | missense, other | 1.0 | F/biochemical | 1.0 | Y 2011 | Disputed | PAEC, PASMC | N/A |
a
MOI, mode of inheritance; AD, autosomal dominant; AR, autosomal recessive; N/A, not applicable.
b
pLOF, predicted loss of function, including nonsense, frameshift, and canonical splice variants.
c
F, function (relevant expression, biochemical function, protein interaction); FA, functional alteration (in patient or non-patient cells); M, model (human or non-human, cell culture/human or non-human); R, rescue (human or non-human, cell culture/human or non-human).
d
BOEC, blood outgrowth endothelial cell; HMVEC, human lung microvascular endothelial cell; PA, pulmonary artery; PAEC, pulmonary artery endothelial cell; PASMC, pulmonary artery smooth muscle cell.
e
LOF, loss of function; GOF, gain of function; N/A, not applicable.