Table 2.
Overview of the detected class 4 and 5 variants in 32 unrelated pulmonary arterial hypertension (PAH) patients.
| Gene | Nucleotide Change | Amino Acid Change | Class | Novel | Reference | Remark Pathogenicity |
|---|---|---|---|---|---|---|
| TBX4 * | c.40_49del | p. (Phe14Argfs*28) | Class 5 a | No | [9] | NA |
| TBX4 * | c.916G > T | p.(Glu306 *) | Class 4 | Yes | NA | Premature stopcodon; not present in gnomAD and ClinVar |
| TBX4 * | c.1112del | p.(Pro371Leufs*8) | Class 5 a | No | [10] | NA |
| BMPR2 | c.(?_-1)_(*1_?)del (entire gene) | p.0 | Class 5 | No | [22] | NA |
| BMPR2 | c.(?_-1)_(76 + 1_77-1)del (exon 1) | p.? e | Class 5 | No | [13] a | |
| BMPR2 | c.76 + 2T > G | p.? e | Class 5 | No | [9] a | NA |
| BMPR2 | c.246A > G | p.(Glu48_Gly83del) (splice defect) | Class 4 | Yes | NA | Defective splice donor site exon 2; use of a cryptic splice donor site in exon 2 (mRNA analysis performed in our lab) |
| BMPR2 | c.348C > G | p.Cys116Trp | Class 4 | Yes | NA | Variant not present in controls (gnomAD). Highly conserved region; AlignGVGD: class C65; SIFT: deletious; PolyPhen2: probably damaging, score 1.000. Variant not present in ClinVar |
| BMPR2 | c.350G > C | p.(Cys117Ser) | Class 5 | No | [13] | NA |
| BMPR2 | c.399del | p.(Pro134Leufs*18) | Class 5 | No | [23] a | NA |
| BMPR2 | c.619dup | p.(Glu207Glyfs* 13) | Class 5 | No | [23] a | NA |
| BMPR2 | c.690del | p.(Val231Cysfs*21) | Class 5 | Yes | [23] a | NA |
| BMPR2 | c.852_852 + 1insA | p.(Gly285Argfs*13) | Class 4 | No | [9] | NA |
| BMPR2 | c.994C > T | p.(Arg332 *) | Class 5 | No | [24] | NA |
| BMPR2 | c.1133G > T | p.(Gly378Val) | Class 5 c | No | [9] | NA |
| BMPR2 | c.1217T > G | p.(Met406Arg) | Class 4 | No | [9] | NA |
| BMPR2 | c.1454A > G | p.(Asp485Gly) | Class 5 | No | [23] a | NA |
| BMPR2 | c.1459G > T | p.(Asp487Tyr) | Class 4 c | Yes | NA | Not present in controls (gnomAD); Highly conserved region; AlignGVGD: class C65; SIFT: deletious; PolyPhen2: probably damaging, score 1.000. ClinVar: 1 entry, likely pathogenic (VCV000212812.2) |
|
BMPR2
(N = 3) |
c.1471C > T | p.(Arg491Trp) | Class 5 | No | [23] a | NA |
| BMPR2 | c.1487G > A | p.(Cys496Tyr) | Class 5 | No | [13] | NA |
| BMPR2 | c.1525G > T | p.(Glu509 *) | Class 5 | No | [25] a | |
| BMPR2 | c.1978G > T | p.(Glu660 *) | Class 5 | No | [25] a | |
| BMPR2 | c.2161C > T | p.(Gln721 *) | Class 5 | Yes | NA | Premature stopcodon. Not present in gnomAD or ClinVar |
| BMPR2 | c.2752C > T | p.(Gln918 *) | Class 5 | No | [25] a | |
| BMPR2 | c.(418 + 1_419-1)_(2866 + 1_2867-1)del (exon 4-12) |
p.? e | Class 5 | No | [23] a | NA |
| BMPR2 | c.(529 + 1_530-1)_(967 + 1_968-1)del (exon 5-7) | p.? e | Class 5 | No | [13] | NA |
| BMPR2 | c.(967 + 1_968-1)_(1128 + 1_1129-1)dup (exon 8) | p.(Val377Ilefs*12) | Class 5 | No | [23] a | A tandem exon duplication was confirmed by Sanger sequencing on cDNA |
| EIF2AK4 | c.1739dup | p.(Arg581Glufs*9) | Class 5 d | No | [26] | NA |
| GDF2 | c.328C > T | p.(Arg110Trp) | Class 4 | No | [9] b | NA |
| GDF2 | c.451C > T | p.(Arg151 *) | Class 4 | No | [16] | NA |
NA not applicable. Reference sequences: BMPR2 NM_001204.6; EIF2AK4 NM_001013703.3; GDF2 NM_016204.3 and TBX4 NM_018488.2. a These patients only tested on BMPR2 and SMAD9 were reported previously in Van der Bruggen et al. [23] and/or Girerd et al. [25]. b This patient was previously reported by Gräf et al. [9].c Both parents tested negative for this variant. d Homozygotic. e An effect on the protein level is expected, but it is not possible to give a reliable prediction of the consequences. * Was previously tested on BMPR2/SMAD9.