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As a result, we identified 16 different mutations in the BMPR2 gene and four different mutations in ACVRL1, the gene for activin receptor-like kinase-1 (ACVRL1). However, no deleterious mutations were found in the remaining 20 genes. In the present study, we provided detailed characterization of the ACVRL1 mutations in four pedigrees, including two novel missense mutations (c.676G&amp;gt;A, p.V226M; c.955G&amp;gt;C, p.G319R) and two recurrent mutations (c.1231C&amp;gt;T, p.R411W; c.1450C&amp;gt;T, p.R484W). Furthermore, we showed that markedly reduced Smad1\/5 phosphorylation levels and reduced activities of luciferase reporters in each of the four ACVRL1 mutant-transfected NIH-3T3 cells. Therefore, our findings demonstrated that missense mutations of ACVRL1 identified in the present study significantly affected the bone morphogenetic protein 9 (BMP-9) pathway, implicating PAH pathogenesis. Detailed genotype\u2013phenotype correlation analysis revealed initial symptoms of hereditary haemorrhagic telangiectasia (HHT) in some of the patients, suggesting the importance of sequencing molecular markers for early identification and intervention of individuals at risk for PAH and potential HHT. We developed a customized exome sequencing system to identify mutations in these PAH-associated genes, and found two novel missense mutations and two recurrent mutations in the ACVRL1 gene in four unrelated Chinese families; we also determined hypomorphic\u00a0alleles using functional studies.<\/jats:p>","DOI":"10.1042\/cs20160247","type":"journal-article","created":{"date-parts":[[2016,6,18]],"date-time":"2016-06-18T02:23:18Z","timestamp":1466216598000},"page":"1559-1569","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Identification of multiple <i>ACVRL1<\/i> mutations in patients with pulmonary arterial hypertension by targeted exome capture"],"prefix":"10.1042","volume":"130","author":[{"given":"Chunmei","family":"Piao","sequence":"first","affiliation":[{"name":"Beijing Anzhen Hospital, Capital Medical University, Beijing, China"},{"name":"Beijing Collaborative Innovation Centre for Cardiovascular Disorders, 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