Mol Genet Genomic Med. 2015 Jul;3(4):354-62. doi: 10.1002/mgg3.147. Epub 2015 Apr 25.

Genetic basis of pulmonary arterial hypertension (PAH) is well recognised but still rarely utilized in diagnostics settings. Diagnostic yield of comprehensive multi-gene panels in PAH is relatively unknown as current knowledge is gathered from studies evaluating only one gene at a time in a heterogenous patient population. Finnish PAH experts and Blueprint Genetics performed a collaborative research project where they screened 21 PAH-patients with the Blueprint Genetics PAH Panel.

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.

Vattulainen S, Aho J, Salmenperä P, Bruce S, Tallila J, Gentile M, Sankelo M, Laitinen T, Koskenvuo JW, Alastalo TP, Myllykangas S.

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