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Title: A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension
Authors: Higasa, Koichiro
Ogawa, Aiko
Terao, Chikashi
Shimizu, Masakazu
Kosugi, Shinji  kyouindb  KAKEN_id  orcid (unconfirmed)
Yamada, Ryo  kyouindb  KAKEN_id  orcid (unconfirmed)
Date, Hiroshi  kyouindb  KAKEN_id
Matsubara, Hiromi
Matsuda, Fumihiko
Author's alias: 日笠, 幸一郎
寺尾, 知可史
小杉, 眞司
山田, 亮
伊達, 洋至
松田, 文彦
Keywords: Clinical genetic testing
Gene-based association study
Next generation sequencing
Pulmonary arterial hypertension
Issue Date: 7-Apr-2017
Publisher: BioMed Central Ltd.
Journal title: BMC Pulmonary Medicine
Volume: 17
Thesis number: 57
Abstract: Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Rights: © The Author(s). 2017 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
DOI(Published Version): 10.1186/s12890-017-0400-z
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