{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:16:12Z","timestamp":1774505772963,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T00:00:00Z","timestamp":1601424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FISPI18\/01233"],"award-info":[{"award-number":["FISPI18\/01233"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008897","name":"Janssen Pharmaceuticals","doi-asserted-by":"publisher","award":["Unrestricted grant"],"award-info":[{"award-number":["Unrestricted grant"]}],"id":[{"id":"10.13039\/100008897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n Contra La Hipertensi\u00f3n Pulmonar","award":["Annual grant"],"award-info":[{"award-number":["Annual grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.<\/jats:p>","DOI":"10.3390\/genes11101158","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T09:41:01Z","timestamp":1601458861000},"page":"1158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-2316","authenticated-orcid":false,"given":"Jair Antonio Tenorio","family":"Casta\u00f1o","sequence":"first","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Hern\u00e1ndez-Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Universitario R\u00edo Hortega, 47012 Valladolid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7523-1474","authenticated-orcid":false,"given":"Natalia","family":"Gallego","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"P\u00e9rez-Olivares","sequence":"additional","affiliation":[{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7018-9844","authenticated-orcid":false,"given":"Nuria","family":"Ochoa Parra","sequence":"additional","affiliation":[{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Arias","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Granda","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo G\u00f3mez","family":"Acebo","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8799-6079","authenticated-orcid":false,"given":"Mauro","family":"Lago-Docampo","sequence":"additional","affiliation":[{"name":"CINBIO, Universidade de Vigo, 36310 Vigo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Galicia Sur, Hospital \u00c1lvaro Cunqueiro, 36213 Vigo, Spain"},{"name":"Centro de Investigaciones Biom\u00e9dicas (CINBIO), 36310 Vigo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Palomino-Doza","sequence":"additional","affiliation":[{"name":"J. CIBERCV, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain"},{"name":"Unidad de Miocardiopat\u00edas Familiares, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"L\u00f3pez Meseguer","sequence":"additional","affiliation":[{"name":"Servicio de Neumolog\u00eda, Hospital Universitario Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Jes\u00fas","family":"del Cerro","sequence":"additional","affiliation":[{"name":"Paediatric cardiology and Grown up Congenital Heart Disease Unit, Hospital Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spanish","family":"PAH Consortium","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"},{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Valverde","sequence":"additional","affiliation":[{"name":"CINBIO, Universidade de Vigo, 36310 Vigo, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Galicia Sur, Hospital \u00c1lvaro Cunqueiro, 36213 Vigo, Spain"},{"name":"Centro de Investigaciones Biom\u00e9dicas (CINBIO), 36310 Vigo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, Melchor Fern\u00e1ndez Almagro, 3, 28029 Madrid, Spain"},{"name":"ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1000 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Escribano-Sub\u00edas","sequence":"additional","affiliation":[{"name":"Unidad Multidisciplinar de Hipertensi\u00f3n Pulmonar, Servicio de Cardiolog\u00eda, Hospital Universitario 12 de Octubre, 28034 Madrid, Spain"},{"name":"J. CIBERCV, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1183\/09031936.00101211","article-title":"Survival in pulmonary hypertension in Spain: Insights from the Spanish registry","volume":"40","author":"Blanco","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Simonneau, G., Montani, D., Celermajer, D.S., Denton, C.P., Gatzoulis, M.A., Krowka, M., Williams, P.G., and Souza, R. (2019). Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. 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