title: Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing.
abstract: The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS-Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing.
authors.affiliation: Pediatric Cardiology, Children's Hospital Helsinki, University of Helsinki and Helsinki University Central Hospital Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Vattulainen
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku Turku, Finland.
authors.forename: Joonas
authors.initials: J
authors.lastname: Aho
authors.affiliation: Blueprint Genetics Helsinki, Finland.
authors.forename: Pertteli
authors.initials: P
authors.lastname: Salmenperä
authors.affiliation: Blueprint Genetics Helsinki, Finland.
authors.forename: Siina
authors.initials: S
authors.lastname: Bruce
authors.affiliation: Blueprint Genetics Helsinki, Finland.
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.affiliation: Blueprint Genetics Helsinki, Finland.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Department of Internal Medicine, Tampere University Hospital Tampere, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Sankelo
authors.affiliation: Department of Pulmonary Diseases and Allergology, Turku University Hospital and University of Turku Turku, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku Turku, Finland ; Blueprint Genetics Helsinki, Finland ; Department of Clinical Physiology and Nuclear Medicine, HUS Medical Imaging Center, Helsinki University of Central Hospital and University of Helsinki Helsinki, Finland.
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.affiliation: Pediatric Cardiology, Children's Hospital Helsinki, University of Helsinki and Helsinki University Central Hospital Helsinki, Finland ; Blueprint Genetics Helsinki, Finland.
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.affiliation: Blueprint Genetics Helsinki, Finland ; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki Helsinki, Finland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Myllykangas
keywords: BMPR2; OS-Seq; genetic diagnostics; genetics; pulmonary arterial hypertension