Clinical details of patient cohort and identified ALK-1 mutations
| Patient number | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| C1 | C2 | C3 | 7685 | 7340 | 7242 | 7253 | 8261 | 7682 | 8259 | 7252 | 7214 | 7684 | 8151 | |
| A, patient alive; AS, appetite suppressant drug treatment; ASD, atrial septal defect; AVM, arteriovenous malformation (diagnosed AVMs listed though not all patients fully screened for AVMs; details available on request); B, Bosentan; C, calcium channel antagonists; CI, cardiac index (defined as cardiac output divided by body surface area; normal range 2.5 to 4.0 l/m2); CO, cardiac output; D, age of death; E, catheterisation not done—echocardiography showed right ventricular systolic pressure of 85 mm Hg; FH, family history of hereditary haemorrhagic telangiectasia; HHT, hereditary haemorrhagic telangiectasia; FH-PPH, sibling of patient with PPH diagnosed with PPH; MPAP, mean pulmonary artery pressure; N, no (not present in patient); ND, not done; NK, not known; P, prostacyclin analogue; PAWP, pulmonary artery wedge pressure (normal range 4 to 12 mm Hg); PE, thromboembolic pulmonary embolism; PPH, primary pulmonary hypertension; PVR, pulmonary vascular resistance (mean pulmonary artery pressure minus pulmonary wedge pressure divided by cardiac output; normal range 1.0 to 2.5 resistance units; a vasodilator response is defined as >20% reduction in pulmonary vascular resistance); S, sildenafil; T, double lung transplant; Y, yes (present in patient). | ||||||||||||||
| Sex | F | F | F | F | F | F | F | F | F | F | F | M | M | F |
| Status, age (years) | A, 80 | D, 16 | D, 65 | D, 54 | A, 56 | A, 44 | NK | A, 41 | D, 18 | A, 29 | A, 26 | A, 49 | A, 62 | A, 64 |
| HHT FH | Y | Y | Y | N | Y | Y | Y | Y | Y | Y | Y | N | Y | Y |
| Epistaxis | Y | Y | Y | N | Y | Y | Y | Y | N | Y | Y | Y | Y | N |
| Telangiectasia | Y | Y | Y | N | Y | Y | Y | Y | N | Y | Y | Y | Y | Y |
| AVM | N | N | N | N | N | Lung | N | N | N | N | N | N | Lung | Lung liver |
| PH age of onset (years) | 77 | 7 | 51 | 51 | 50 | 39 | 19 | 39 | 17 | 27 | 21 | 46 | 57 | 59 |
| MPAP (mm Hg) | 54 | 55 | 47 | 55 | 54 | 49 | 44 | 48 | 40 | 54 | 71 | 48 | 41 | |
| CO (l/min) | 3.4 | NK | 4.8 | 2.5 | 5.9 | 4.2 | 4.9 | 1.8 | 3.1 | NK | 4.8 | 6.7 | 7.0 | |
| CI (l/min/m2) | 2.1 | 3.2 | 2.8 | NK | E | 3.0 | 3.0 | 1.3 | 1.8 | NK | 2.5 | 3.8 | 4.0 | |
| PAWP (mm Hg) | 11 | 8 | 10 | 10 | 12 | 10 | 10 | NK | 3.0 | 8 | 15 | 10 | 17 | |
| PVR (resistance units) | 12.4 | 20.3 | 7.7 | 18 | 7.1 | 9.3 | 6.9 | NK | 11.9 | 9.2 | 11.6 | 5.7 | 3.4 | |
| Vasodilator response | Y | N | N | N | N | N | N | N | N | N | N | N | ND | |
| Treatment | C, B | C | P | P | P, B | P | P | S | P, B | T | C | B, S | ||
| Possible risk factors | AS | Repaired ASD, FH-PPH | PE | |||||||||||
| Mutation | ||||||||||||||
| Gene | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ALK-1 | ENG | ENG | |||
| Exon | 5 | 6 | 7 | 7 | 8 | 8 | 8 | 8 | 10 | 5 | 10 | |||
| Nucleotide change | ND – (no DNA) | ND – (no DNA) | ND – (no DNA) | 536 A>C | 632 G>A | 1031 G>A | 1031 G>A | 1120 C>T | 1121 G>A | 1196 G>C | 1232 G>A | 1460 A>C | del 682–686 | delT 1334 |
| Amino acid change | D179A | G211D | C344Y | C344Y | R374W | R374Q | W399S | R411Q | K487T | S228fs+102AA 331X | M445fs+44AA 490X | |||
| Restriction enzyme | Msc I | Bgl I | – | – | – | – | – | Hpa II | Mbo II | – | – | |||
| Previous reports | Novel | Novel | 12 | 12 | 13, 14, 15 | 14 | Novel | 2, 13, 14, 16 | Novel | Novel | Novel | |||