title: A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kawara-cho 53, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. higasa@genome.med.kyoto-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.affiliation: Department of Clinical Science, National Hospital Organization Okayama Medical Center, Okayama, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kawara-cho 53, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kawara-cho 53, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Medical Ethics/Medical Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kosugi
authors.affiliation: Statistical Genetics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Department of Clinical Science, National Hospital Organization Okayama Medical Center, Okayama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kawara-cho 53, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007564:Japan; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D012307:Risk Factors
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Clinical genetic testing; Gene-based association study; Next generation sequencing; Pulmonary arterial hypertension