Table 3.
(Likely) pathogenic variants in non-BMPR2 genes
| Gene | Exon | DNA | Protein | CADD score | GnomAD count | Diagnosis |
|---|---|---|---|---|---|---|
| ACVRL1 | 3 | c.205T > C | p.(Cys69Arg) | 25 | 0 | HPAH (HHT) |
| ACVRL1 | 5 | c.578T > C | p.(Leu193Pro) | 31 | 0 | HPAH (HHT) |
| ACVRL1 | 10 | c.1450C > T | p(Arg484Trp) | 26 | 0 | HPAH |
| AQP1 | 1 | c.376C > T | p.(Arg126Cys) | 26 | 0 | HPAH |
| ATP13A3 | 14 | c.1540C > T | p.(Gln514*) | NA (Nonsense) | 0 | Drugs and toxins induced PAH [17] |
| EIF2AK4 | 1 | c.1A > T | p.(Met1?)b | NA (Start loss) | 0 | PVOD |
| EIF2AK4 | 6 | c.595-1G > A | intronic b | 35 | 0 | PVOD |
| EIF2AK4 | 6 | c.641delA | p.(Lys241Argfs*21)a | NA (Deletion) | 0 | PVOD |
| EIF2AK4 | 9 | c.1362C > A | p.(Cys454*)b | NA (Nonsense) | 0 | CTD-APAH |
| EIF2AK4 | 21 | c.2965C > T | p.(Arg989Trp)b | 31 | 5 | PVOD |
| EIF2AK4 | 24 | c.3380C > T | p.(Ala1127Val)b | 26 | 0 | PVOD |
| EIF2AK4 | 25 | c.3443T > C | p.(Leu1148Ser)b | 31 | 0 | CTD-APAH |
| EIF2AK4 | 31 | c.4260G > A | p.(Trp1420*)a | NA (Nonsense) | 0 | PVOD |
| ENG | 12 | c.1646G > A | p.(Cys549Tyr) | 26 | 0 | IPAH |
| GDF2 | 2 | c.857dupA | p.(Leu287Alafs*11) | NA (Duplication) | 0 | IPAH |
| GDF2 | 1 | c.329G > A | p.(Arg110Gln) | 32 | 0 | HPAH |
| KCNK3 | 2 | c.641T > C | p.(Leu214Pro) | 27 | 0 | IPAH |
| KCNK3 | 2 | c.340G > A | p.(Ala114Thr) | 26 | 0 | HPAH |
| KCNK3 | 1 | c.250_267dup TTCTACTTCGCCATCACC | p.(Val84_Thr89dup)a | NA (Duplication) | 0 | HPAH |
| SMAD9 | 2 | c.29T > C | p.(Leu10Pro) | 27 | 0 | HPAH |
| SOX17 | 1 | c.273_277delAGACC | p.(Asp92Alafs*68) | NA (Deletion) | 0 | IPAH |
| SOX17 | 2 | c.413G > C | p.(Arg138Pro) | 33 | 0 | HPAH |
| SOX17 | 2 | c.1245A > G | p.(*415Trp) | Stop loss | 0 | CHD-APAH |
| SOX17 | 2 | c.499_520del | p.(Leu167Trpfs*213) | NA (Deletion) | 0 | IPAH |
| TBX4 | 2 | c.278G > A | p.(Gly93Asp) | 33 | 0 | IPAH |
| TBX4 | 3 | c.400delT | p.(Trp134Glyfs*38) | NA (Deletion) | 0 | IPAH |
| TBX4 | 6 | c.709_710ins56bp | p.(Gln237Profs*18)b | NA (Insertion) | 0 | IPAH |
| TBX4 | 8 | c.1543G > A | p.(Glu515Lys)b | 24 | 0 | IPAH |
aHomozygous variant
bTogether with 2nd variant in same gene
APAH associated pulmonary arterial hypertension; CADD score Combined Annotation Dependent Depletion score, summation score based on different in silico prediction programmes, CHD congenital heart disease, CTD connective tissue disease, GnomAD Genome Aggregation Consortium Database with n = 125,748 samples, HHT hereditary haemorrhagic telangiectasia, HPAH heritable pulmonary arterial hypertension, IPAH idiopathic pulmonary arterial hypertension, PVOD pulmonary veno-occlusive disease. Used Ensembl transcripts and respective reference sequences: ACVRL1: ENST00000267008.3, NM_000020; AQP1: ENST00000311813.11, NM_198098.3; ATP13A3: ENST00000256031.4, NM_024524.3; EIF2AK4: ENST00000263791.1 NM_001013703; ENG: ENST00000373203.2, NM_001114753; GDF2: ENST00000249598, NM_016204.2; KCNK3: ENST00000302909, NM_002246.2; SMAD9: ENST00000379826.1, NM_001127217; SOX17: ENST00000297316, NM_022454.3; TBX4: ENST00000240335.1, NM_018488.3