Table 1. Novel pathogenic BMPR2 mutations identified in this analysis.
| Location | Mutation category | Nucleotide change | Amino acid change | Frequency in this study | Clinical classification |
|---|---|---|---|---|---|
| 5′UTR | Transition | c.-669G>A | p.? | 3 | I, NK, P |
| 5′UTR to exon 1 | Deletion | c. ?_-540_76+?del | p.? | 1 | NK |
| 5′UTR to exon 13 | Deletion | c? -540 3117+?del | p.? | 1 | NK |
| Exon 1 | Deletion | c.1-? 76+?del | p.? | [3] | I, NK (n=2) |
| Exon 1 | Frameshift | c.9dupC | p.S4Lfs*34 | 1 | NK |
| Exon 1 | Nonsense | c.16C>T | p.Q6* | 2 | I, NK |
| Exon 1 | Nonsense | c.38G>A | p.W13* | 1 | H |
| Exon 1 | Nonsense | c.48G>A | p.W16* | 1 | I |
| Intron 1 | Splice-site | c.76+1G>T | p.? | 1 | H |
| Intron 1 | Splice-site | c.76+2T>C | p.? | 1 | NK |
| Intron 1 | Splice-site | c.77-1G>A | p.A26Efs*9 | 1 | H |
| Exons 2-5 | Deletion | c.77-?_621+?del | p.? | 1 | H |
| Exons 2-9 | Deletion | c.77-?_1276+?del | p.? | 1 | NK |
| Exon 2 | Nonsense | c.82C>T | p.Q28* | 1 | NK |
| Exon 2 | Missense | c.178t>c | p.C60R | 1 | NK |
| Exon 2 | Missense | c.196t>g | p.C66G | 1 | NK |
| Exon 2 | Frameshift | c.236_238delinsAAAAGGGGACA | p.L79Qfs*5 | 1 | NK |
| Exon 2 | Frameshift | c.246dupA | p.G83Rfs*15 | 1 | H |
| Intron 2 | Splice-site | c.247+1G>A | p.? | 1 | NK |
| Exon 3 | Deletion | c.248-?_418+?del | p.? | [4] | I (n=3), NK |
| Exon 3 | Duplication | c.248-?_418+?dup | p.? | 1 | H |
| Exon 3 | Missense | c.280T>G | p.C94G | 1 | NK |
| Exon 3 | Frameshift | c.339_340insAA | p.R114Nfs*39 | 1 | H |
| Exon 3 | Frameshift | c.345_346delCT | p.F115Lfs*4 | 1 | NK |
| Exon 3 | Missense | c.350G>A | p.C117Y | 1 | NK |
| Exon 3 | Frameshift | c.353delG | p.C118Lfs*34 | 1 | NK |
| Exon 3 | Missense | c.354T>G | p.C118W | 1 | I |
| Exon 3 | Missense | c.377A>G | p.N126S | 1 | NK |
| Exon 4 | Deletion | c.419-?_529+?del | p.? | 1 | NK |
| Exons 4-7 | Deletion | c.419-?_967+?del | p.? | [2] | I, NK |
| Exons 4-10 | Deletion | c.419-?_1413+?del | p.? | 1 | NK |
| Exon 4 | Frameshift | c.435delT | p.F145Lfs*7 | 1 | NK |
| Exon 4 | Nonsense | c.439C>T | p.R147* | 1 | H |
| Exon 4 | Nonsense | c.482T>A | p.L161* | 1 | I |
| Exon 5 | Deletion | c.530-?_621+?del | p.? | 1 | NK |
| Exon 5 | Nonsense | c.541C>T | p.Q181* | 1 | H |
| Exon 6 | Nonsense | c.637C>T | p.R213* | 1 | H |
| Exon 6 | Nonsense | c.642T>G | p.Y214* | 1 | NK |
| Exon 6 | Frameshift | c.673 679delCGTCCAG | p.R225Lfs*3 | 1 | H |
| Exon 6 | Nonsense | c.727G>T | p.E243* | 1 | I |
| Exon 6 | Frameshift | c.795_796delinsTT | p.E265 L1038delinsD | 1 | NK |
| Intron 6 | Splice-site | c.853-2A>G | p.? | 1 | NK |
| Intron 6 | Splice-site | c.853-1G>A | p.? | 1 | NK |
| Exon 7 | Nonsense | c.860T>A | p.L287* | 1 | H |
| Exon 7 | Nonsense | c.872T>G | p.L291* | 1 | NK |
| Exon 7 | Nonsense | c.893G>A | p.W298* | 1 | NK |
| Exon 7 | Frameshift | c.894_895dupGG | p.V299Gfs*2 | 1 | H |
| Exon 7 | Frameshift | c.961delC | p.R321Efs*14 | 1 | NK |
| Intron 7 | Splice-site | c.967+2T>C | p.? | 1 | H |
| Intron 7 | Splice-site | c. 968-3 C>G | p.? | 1 | NK |
| Intron 7 | Splice-site | c.968-1G>T | p.? | 1 | NK |
| Exon 8 | Nonsense | c.994C>T | p.R332* | 1 | NK |
| Exon 8 | Frameshift | c.1011_1015delAAATG | p.R337Sfs*6 | 1 | I |
| Exon 8 | Frameshift | c.1060delC | p.L354Cfs*3 | 1 | NK |
| Exon 8 | Nonsense | c.1126G>T | p.E376* | 2 | I, NK |
| Exon 9 | Frameshift | c. 1129-1_1129dupGG | p.V377Gfs*13 | 1 | I |
| Exon 9 | Frameshift | c.1141dupA | p.R381Kfs*18 | 1 | H |
| Exon 9 | Missense | c.1156G>C | p.E386Q | 1 | NK |
| Exon 9 | Missense | c.1220a>c | p.Y407S | 1 | NK |
| Exon 9 | Nonsense | c.1221t>g | p.Y407* | 1 | H |
| Exon 9 | Frameshift | c.1268dupT | p.F424Lfs*24 | 1 | NK |
| Exon 9 | Missense | c.1276g>c | p.G426R | 1 | H |
| Intron 9 | Splice-site | c. 1277-9 A>C | p.? | 1 | H |
| Intron 9 | Splice-site | c.1277-8a>g | p.? | 1 | NK |
| Exon 10 | Frameshift | c.1279delG | p.E427Nfs*47 | 1 | NK |
| Exon 10 | Frameshift | c.1285_1286insGGATT | p.V429Gfs*47 | 2 | I, NK |
| Exon 10 | Frameshift | c.1293_1300delGTACCAGA | p.E431Dfs*14 | 1 | NK |
| Exon 10 | Frameshift | c.1371delA | p.K457Nfs*17 | 1 | H |
| Exon 10 | Nonsense | c.1398g>a | p.W466* | 1 | NK |
| Exon 10 | Nonsense | c.1402g>t | p.E468* | 1 | H |
| Exon 11 | Frameshift | c.1426_1450del | p.L476Gfs*22 | 1 | NK |
| Exon 11 | Nonsense | c.1441g>t | p.E481* | 1 | NK |
| Exon 11 | Nonsense | c.1451g>a | p.W484* | 1 | H |
| Exon 11 | Missense | c.1453g>a | p.D485N | 1 | P |
| Exon 11 | Nonsense | c.1456c>t | p.Q486* | 1 | H |
| Exon 11 | Frameshift | c.1477dupA | p.T493Nfs*6 | 1 | NK |
| Exon 11 | Missense | c.1486t>c | p.C496R | 1 | NK |
| Intron 11 | Splice-site | c. 1587-7_1587-4delCTTT | p.? | 1 | I |
| Exon 12 | Nonsense | c.1629t>g | p.Y543* | 1 | I |
| Exon 12 | Nonsense | c.1750c>t | p.R584* | 1 | NK |
| Exon 12 | Nonsense | c.1789C>T | p.R597* | 1 | NK |
| Exon 12 | Nonsense | c.1969C>T | p.Q657* | 2 | I, NK |
| Exon 12 | Nonsense | c.1981g>t | p.E661* | 1 | NK |
| Exon 12 | Frameshift | c.2291dupA | p.N764Kfs*49 | 1 | H |
| Exon 12 | Frameshift | c.2303 2309delAGCCCCG | p.E768Gfs*2 | 1 | NK |
| Exon 12 | Frameshift | c.2308delC | p.R770Gfs*2 | 2 | NK (n=2) |
| Exon 12 | Frameshift | c.2484delG | p.T829Qfs*10 | 1 | H |
| Exon 12 | Nonsense | c.2533G>T | p.E845* | 1 | I |
| Exon 12 | Nonsense | c.2695C>T | p.R899* | 3 | H (n=2), NK |
| Exon 12 | Nonsense | c.2730T>A | p.C910* | 1 | H |
| Exon 12 | Nonsense | c.2737C>T | p.Q913* | 1 | I |
†
GenBank reference sequence and version number for BMPR2: NM_001204.6; numbering is from +1 as A of the ATG initiation codon
‡
Total number of independent cases. Frequencies in square brackets denote chromosomal rearrangements for which the breakpoints are unknown and may therefore represent distinct mutations
Key to abbreviations: H: heritable pulmonary arterial hypertension; I: idiopathic pulmonary arterial hypertension; NK: not known; P: pediatric pulmonary arterial hypertension