{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:28:33Z","timestamp":1787041713385,"version":"build-2736575974"},"reference-count":13,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>RASopathies are a group of genetic disorders caused by germline variants affecting the RAS\/MAPK pathway. Their shared phenotypic features\u2014craniofacial anomalies, cardiac defects, cutaneous findings, neurodevelopmental issues, and cancer predisposition\u2014make diagnosis challenging, especially since most lack standardized clinical criteria. This study aimed to develop a practical diagnostic algorithm based on high-frequency Human Phenotype Ontology (HPO) features. Key clinical variables for each RASopathy were identified through HPO, PubMed, and GeneReviews. Only findings present in 80\u201399% of cases or supported by expert consensus were included. A decision-tree algorithm was constructed and preliminarily evaluated using a blinded cohort of 50 individuals with confirmed molecular diagnoses. Patients were eligible for inclusion if they met the following criteria: (1) molecularly confirmed diagnosis of a RASopathy by next-generation sequencing identifying a pathogenic or likely pathogenic variant; (2) availability of complete phenotypic records in the institutional clinical database; and (3) age at evaluation between 0 and 18 years. Patients were excluded if phenotypic data were incomplete or if molecular confirmation was absent. The algorithm integrates phenotypic patterns and genotype\u2013phenotype correlations. Validation showed 78% accuracy (95% CI: 64.0\u201388.4%) for clinical diagnosis and 66% accuracy (95% CI: 51.2\u201378.8%) for molecular prediction. To our knowledge, this is the first HPO-based diagnostic algorithm for the clinical and molecular approach to RASopathies. It provides a structured, accessible tool to improve early recognition and guide molecular testing, particularly for the RASopathy subtypes represented in the validation cohort. Further external validation including underrepresented subtypes is required.<\/jats:p>","DOI":"10.3390\/ijms27167348","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:42:17Z","timestamp":1786974137000},"page":"7348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proposal of an Algorithm for the Clinical and Molecular Diagnosis of RASopathies Based on HPO Nomenclature"],"prefix":"10.3390","volume":"27","author":[{"given":"Fernanda","family":"Meneses","sequence":"first","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad Icesi, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Quintero","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad Icesi, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Lores","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias B\u00e1sicas, Facultad de Ciencias de la Salud, Pontificia Universidad Javeriana, Cali 760032, Colombia"},{"name":"Unidad de Medicina Gen\u00f3mica y Gen\u00e9tica, Cl\u00ednica Imbanaco Grupo Quironsalud, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3664-6387","authenticated-orcid":false,"given":"Eidith","family":"G\u00f3mez-Pineda","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad Icesi, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9424-7554","authenticated-orcid":false,"given":"Diana","family":"Ram\u00edrez-Monta\u00f1o","sequence":"additional","affiliation":[{"name":"Unidad de Medicina Gen\u00f3mica y Gen\u00e9tica, Cl\u00ednica Imbanaco Grupo Quironsalud, Cali 760032, Colombia"},{"name":"Hospital Universitario del Valle, Cali 76003, Colombia"},{"name":"Departamento de Morfolog\u00eda, Facultad de Ciencias de la Salud, Universidad del Valle, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3002-7071","authenticated-orcid":false,"given":"Estephania","family":"Candelo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Head-Neck Surgery, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-0439","authenticated-orcid":false,"given":"Harry","family":"Pachajoa","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica M\u00e9dica, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"},{"name":"Centro de Investigaci\u00f3n en Anomal\u00edas Cong\u00e9nitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali 760031, Colombia"},{"name":"Centro de Investigaciones Cl\u00ednicas, Fundaci\u00f3n Valle del Lili, Cali 760032, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","article-title":"The RASopathies","volume":"14","author":"Rauen","year":"2013","journal-title":"Annu. 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Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:10:07Z","timestamp":1787040607000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":13,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167348"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167348","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}