{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T09:57:36Z","timestamp":1763200656863,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ISCIII (Ministry of Health of Spain)","award":["PI-3569","PI-2734"],"award-info":[{"award-number":["PI-3569","PI-2734"]}]},{"name":"European Union","award":["PI-3569","PI-2734"],"award-info":[{"award-number":["PI-3569","PI-2734"]}]},{"name":"FIBHULP","award":["PI-3569","PI-2734"],"award-info":[{"award-number":["PI-3569","PI-2734"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Wolf\u2013Hirschhorn syndrome (WHS; OMIM #194190) is a rare neurodevelopmental disorder, caused by deletions in the distal short arm of chromosome 4. It is characterized by developmental delay, epilepsy, intellectual disability, and distinctive facial dysmorphism. Clinical presentation varies widely, complicating prognosis and individualized care. Methods: We assembled a cohort of 140 individuals with genetically confirmed WHS from Spain and Latin-America, and developed and validated a multidimensional, Clinician-Reported Outcome Assessment (ClinRO) based on the Global Functional Assessment of the Patient (GFAP), derived from standardized clinical questionnaires and weighted by HPO (Human Phenotype Ontology) term frequencies. The GFAP score quantitatively captures key functional domains in WHS, including neurodevelopment, epilepsy, comorbidities, and age-corrected developmental milestones (selected based on clinical experience and disease burden). Results: Higher GFAP scores are associated with worse clinical outcomes. GFAP showed strong correlations with deletion size, presence of additional genomic rearrangements, sex, and epilepsy severity. Ward\u2019s clustering and discriminant analyses confirmed GFAP\u2019s discriminative power, classifying over 90% of patients into clinically meaningful groups with different prognoses. Conclusions: Our findings support GFAP as a robust, WHS-specific ClinRO that may aid in stratification, prognosis, and clinical management. This tool may also serve future interventional studies as a standardized outcome measure. Beyond its clinical utility, GFAP also revealed substantial social implications. This underscores the broader socioeconomic burden of WHS and the potential value of GFAP in identifying high-support families that may benefit from targeted resources and services.<\/jats:p>","DOI":"10.3390\/genes16070820","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T10:46:05Z","timestamp":1752662765000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinician-Based Functional Scoring and Genomic Insights for Prognostic Stratification in Wolf\u2013Hirschhorn Syndrome"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-2659","authenticated-orcid":false,"given":"Juli\u00e1n","family":"Nevado","sequence":"first","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"},{"name":"ITHACA-European Reference Network-Hospital La Paz, 28046 Madrid, Spain"},{"name":"Facultad HM de Ciencias de la Salud, Universidad Camilo Jos\u00e9 Cela e Instituto de Investigaci\u00f3n Sanitaria HM Hospitales, 28015 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Blanco-Lago","sequence":"additional","affiliation":[{"name":"Servicio de Neuropediatr\u00eda, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-447X","authenticated-orcid":false,"given":"Cristina","family":"Bel-Fenell\u00f3s","sequence":"additional","affiliation":[{"name":"Departamento de Investigaci\u00f3n y Psicolog\u00eda en Educaci\u00f3n, Facultad de Educaci\u00f3n, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1078-2328","authenticated-orcid":false,"given":"Adolfo","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Econom\u00eda Financiera y Actuarial y Estad\u00edstica, Facultad de Comercio y Turismo, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda A.","family":"Mori-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-2230","authenticated-orcid":false,"given":"Chantal","family":"Biencinto-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Departamento de Investigaci\u00f3n y Psicolog\u00eda en Educaci\u00f3n, Facultad de Educaci\u00f3n, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4074-6870","authenticated-orcid":false,"given":"Ignacio","family":"M\u00e1laga","sequence":"additional","affiliation":[{"name":"Servicio de Neuropediatr\u00eda, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-0439","authenticated-orcid":false,"given":"Harry","family":"Pachajoa","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones en Anomal\u00edas Cong\u00e9nitas y Enfermedades Raras, Universidad ICESI, Cali 760031, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5601-4813","authenticated-orcid":false,"given":"Elena","family":"Mansilla","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2393-7800","authenticated-orcid":false,"given":"Fe A.","family":"Garc\u00eda-Santiago","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Barr\u00faz","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-2316","authenticated-orcid":false,"given":"Jair A.","family":"Tenorio-Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"},{"name":"ITHACA-European Reference Network-Hospital La Paz, 28046 Madrid, Spain"},{"name":"Facultad HM de Ciencias de la Salud, Universidad Camilo Jos\u00e9 Cela e Instituto de Investigaci\u00f3n Sanitaria HM Hospitales, 28015 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yolanda","family":"Mu\u00f1oz-G\u00aaPorrero","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2110-2703","authenticated-orcid":false,"given":"Isabel","family":"Vallcorba","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-4825","authenticated-orcid":false,"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica 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