Table 2.
Summary of main clinical findings associated with genetic variants in paediatric PAH.
| Gene (protein) symbol | OMIM reference | PAH group (%) | Inheritance pattern | Associated clinical features | Probands reported (n) | Age of diagnosis (y) | mPAP (mmHg) | PVR (WU) or PVRi (WU m2) | mPWP (mmHg) | CI (L/min/m2) | Drug response | Recent key references |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ABCC8 (SUR1) | 600509 | IPAH (62%); APAH-CHD (23%); HPAH (15%) | AD | >Gene also linked to familial hyperinsulinaemic hypoglycaemia, transient/permanent neonatal diabetes mellitus >A nonsense variant has been reported in a patient with PPHN and hypoglycaemia |
13 | 8.0 ± 6.0 (n = 11) | 51.2 ± 8.0 (n = 5) | 20.1 ± 6.6 WU m2 (n = 5) | 8.0 ± 0 (n = 3) | 2.8 ± 0.61 (n = 4) | >Activation of SUR1 may be a potential therapeutic target for PAH >Diazoxide may resolve symptoms in adults but can lead to PH in hypoglycaemic infants |
29, 30, 63• |
| ACVRL1 (ALK1) | 601284 | PAH-HHT (44%); IPAH (38%); HPAH (18%) | AD | HHT type 2 (epistaxis, mucocutaneous telangiectases, visceral AVMs) | 40 | 8.2 ± 5.4 (n = 40) | 67.0 ± 17.8 (n = 30) | 22.4 ± 12.5 WU (n = 12); 20.0 ± 12.2 WU m2 (n = 16) |
9.0 ± 3.6 (n = 23) | 3.2 ± 1.0 (n = 28) | 96% (23/24) have no response to acute vasodilator test | 10, 64 |
| ATP13A3 | 610232 | HPAH (50%); IPAH (25%); APAH-CHD (25%) | AD; AR | >Biallelic variants are linked to a severe, early-onset form of PAH >A heterozygous variant has been reported in one child with PAH and secundum ASD |
4 | 2.7 ± 3.0 (n = 6) | 46 ± 9.7 (n = 4) | 19.3 ± 10.6 WU (n = 3) | nd | 1.7 (n = 1) | >Biallelic variants are associated with rapidly progressive refractory PAH >Pre-emptive Potts shunt has been used successfully in one case |
21, 23, 65 |
| BMP10 | 608748 | IPAH (50%); APAH-CHD (50%) | AD | – | 2 | 7.0 ± 4.0 (n = 2) | 35 (n = 1) | nd | nd | 3.5 (n = 1) | – | 17•, 18, 21 |
| BMPR1B | 603248 | IPAH (75%); APAH-CHD (25%) | AD | >Gene also linked to brachydactyly >One paediatric case reported with PAH and ASD |
4 | 10.3 ± 2.7 (n = 4) | 88.5 ± 22.5 (n = 2) | nd | 9 (n = 1) | 2.8 ± 0.8 (n = 2) | – | – |
| BMPR2 | 600799 | IPAH (51%); HPAH (39%); APAH-CHD (10%) | AD | – | >130 | 10.2 ± 5.0 (n = 109) | 69.8 ± 15.0 (n = 31) | 19.0 ± 10.8 WU (n = 6); 22.1 ± 11.9 WU m2 (n = 21) |
9.4 ± 2.6 (n = 20) | 3.2 ± 1.4 (n = 24) | 75% (12/16) have no response to acute vasodilator test | 10, 16, 56 |
| CAV1 | 601047 | HPAH (60%); IPAH (20%); APAH (20%) | AD | >Gene also linked to congenital lipodystrophies >A de novo variant has been reported in one case of neonatal lipodystrophy, PAH and PAVM |
5 | 4.2 ± 3.0 (n = 5) | 50.5 ± 10.4 (n = 4) | 11.1 ± 4.7 WU m2 (n = 4) | 11 (n = 1) | 3.2 ± 0.05 (n = 3) | 100% (4/4) paediatric cases responsive to acute vasodilator challenge (but adult relatives with the same variant were not) | – |
| EIF2AK4 (GCN2) | 609280 | PVOD/PCH (91%); IPAH (9%) | AR | Some reports of biallelic EIF2AK4 variants in clinically diagnosed paediatric PAH | 11 | 15.1 ± 2.0 (n = 8) | 52.3 ± 20.1 (n = 7) | 11.3 ± 6.1 WU m2 (n = 3) | 6.3 ± 1.7 (n = 3) | 2.6 ± 1.3 (n = 3) | Use of vasodilators associated with life-threatening pulmonary oedema | 58, 62 |
| ENG | 131195 | PAH-HHT (60%); IPAH (20%); APAH-CHD (20%) | AD | HHT type 1 (telangiectasia and PAVMs, epistaxis) | 5 | 8.2 ± 6.7 (n = 5) | 46.3 ± 5.0 (n = 3) | 10.5 ± 4.3 WU (n = 3) | 7.3 ± 3.3 (n = 3) | 3.2 ± 0.5 (n = 3) | – | [10] |
| GDF2 (BMP9) | 605120 | IPAH (78%); PAH-HHT (22%) | AD; AR | >HHT type 5 (telangiectasia, AVMs, epistaxis); PAVMs >Homozygous variants are also associated with ‘HHT-like’ facial telangiectases and diffuse PAVMs |
9 | 8.4 ± 5.6 (n = 7) | 58.8 ± 21.3 (n = 6) | 13.4 ± 10.9 WU (n = 6) | 7.0 ± 0.8 (n = 3) | 4.5 ± 2.0 (n = 6) | – | 15••, 17•, 19, 20 |
| KCNK3 (TASK1) | 603220 | IPAH (57%); HPAH (43%) | AD | – | 9 | 6.4 ± 3.8 (n = 6) | 97.0 ± 10.0 (n = 2) | 44 ± 8.0 WU (n = 2) | 10 (n = 1) | 2.4 ± 0.3 (n = 2) | – | 26, 27, 29 |
| NOTCH3 | 600276 | IPAH | AD | >Heterozygous variants are a major cause of CADASIL >Gene is also linked to lateral meningocele syndrome |
4 | 4.0 ± 0 (n = 2) | 68.5 ± 1.5 (n = 2) | nd | 12 (n = 1) | 2.9 (n = 1) | – | – |
| SMAD9 (SMAD8) | 603295 | IPAH (43%); APAH-CHD (43%); HPAH (14%) | AD | – | 7 | 5.7 ± 4.6 (n = 7) | 70.0 ± 17 (n = 2) | 24.9 ± 12.5 WU m2 (n = 2) | 6.0 ± 0 (n = 2) | 3.2 ± 1.1 (n = 2) | – | – |
| SOX17 | 610928 | APAH-CHD (63%); IPAH (25%); HPAH (12%) | AD | >Strongly linked to APAH-CHD >Gene may also be associated with vesicoureteral reflux |
15 | 4.9 ± 3.6 (n = 18) | 34.5 ± 2.5 (n = 2) | 8.0 ± 1.0 WU (n = 2) | 5.5 ± 0.5 (n = 2) | nd | – | 40•, 44 |
| TBX4 | 601719 | IPAH (33%); APAH-CHD (31%); PAH-SPS (29%); HPAH (8%); other (4%) | AD | >Small patella syndrome with/without PAH >Abnormal distal lung development >Cardiac and skeletal malformations >Copy number variants (CNVs) are more commonly associated with developmental delay |
60 (incl. 10 cases with PPHN) | 4.3 ± 4.8 (n = 52) | 59.8 ± 24.4 (n = 24) | 17.5 ± 15.5 WU m2 (n = 25) | 9.5 ± 4.5 (n = 18) | 3.9 ± 2.2 (n = 24) | 35% (8/23) patients demonstrate partial vasoreactivity | 25••, 51•, 52, 53 |
Table summarising the clinical features, onset and severity of disease related to genes reported to cause paediatric PAH. Haemodynamic data are provided as mean ± standard deviation at diagnosis for n patients (includes some related individuals). AVMs: arteriovenous malformations; CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CI: cardiac index; mPAP: mean pulmonary artery pressure; mPWP: mean pulmonary wedge pressure; nd: no data available; OMIM: Online Mendelian Inheritance in Man (https://www.omim.org); PAVMs: pulmonary arteriovenous malformations; PVR(i): pulmonary vascular resistance (index).