The online version of this article (doi:10.1186/s12890-017-0400-z) contains supplementary material, which is available to authorized users.
Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance.
To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls.
A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population.
The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.
Additional file 1: Table S1. Summary of mapping statistics. (PDF 22 kb)12890_2017_400_MOESM1_ESM.pdf
Additional file 2: Figure S1. Large deletion found in the patient in family 8. (a) The large deletion was supported by depth of coverage and discordant paired-end reads. (b) The length of the deletion was approximately 6.5 kilobases and spanned the entire region of exon 3. Breakpoints of the large heterozygous deletion were located in the Alu repeat sequences, which were supported by read depths and paired-end reads spanning the long region. (PDF 529 kb)12890_2017_400_MOESM2_ESM.pdf
Additional file 3: Figure S2. Possible pathogenic variants found in the intron of BMPR2 in family 4. A rare three base insertion (GGG) at 10 bases upstream from exon 10 creates identical sequences around the canonical splicing site (ACAGGG). By the insertion, an out-of-frame protein could be translated due to the new splice acceptor site. (PDF 411 kb)12890_2017_400_MOESM3_ESM.pdf
Additional file 4: Figure S3. Creation of the new splice acceptor site by the three base insertion (NM_001204.6:c.1277-10_1277-9insGGG) predicted from in silico programs. (PDF 218 kb)12890_2017_400_MOESM4_ESM.pdf
Additional file 5: Figure S4. Disruption of wild type acceptor site by the single nucleotide variants (c.853-2A > G) predicted from in silico programs. (PDF 184 kb)12890_2017_400_MOESM5_ESM.pdf
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- A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension
- BioMed Central
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