{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T21:52:59Z","timestamp":1777931579821,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phelan\u2013McDermid syndrome (PMS; #MIM: 606232) is a rare neurodevelopmental disorder primarily caused by the haploinsufficiency of the SHANK3 gene, most often due to deletions encompassing the gene or single nucleotide variants within it. Individuals with PMS display a wide range of clinical abnormalities and considerable genetic heterogeneity. This study aims to investigate genotype\u2013phenotype correlations in a cohort of 213 individuals with PMS and to identify novel candidate genes, beyond SHANK3, that may contribute to the syndrome\u2019s diverse clinical manifestations. Unsupervised clustering based on deletion size and Global Functional Assessment of the Patient (GFAP, previously described and developed by our group), along with additional analytical approaches, were employed to explore genotype\u2013phenotype relationships. Deletion size within the 22q13.3 region emerged as a major determinant of phenotype, with larger deletions associated with more severe global functional impairment. Furthermore, CERK, TBC1D22A, CELSR1, and GRAMD4 were identified as candidate genes within 22q13.3, potentially contributing to core PMS phenotypes, and their putative interactions were explored. Our findings support the central role of SHANK3 in PMS, while also indicating that it does not account for the full phenotypic spectrum. This study underscores the variable impact of distinct genetic alterations in PMS and proposes additional loci implicated in its pathogenesis. These insights may inform future therapeutic strategies, emphasizing the importance of patient stratification and precision medicine.<\/jats:p>","DOI":"10.3390\/ijms26104653","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T06:40:23Z","timestamp":1747118423000},"page":"4653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genotype\u2013Phenotype Associations in Phelan\u2013McDermid Syndrome: Insights into Novel Genes Beyond SHANK3"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-2659","authenticated-orcid":false,"given":"Julian","family":"Nevado","sequence":"first","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"CIBERER\u2014Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"},{"name":"ITHACA-European Reference Network-Hospital La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"Escalada","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 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, Paseo de la Castellana 261, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Adan","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-2316","authenticated-orcid":false,"given":"Jair","family":"Tenorio-Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"CIBERER\u2014Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"},{"name":"ITHACA-European Reference Network-Hospital La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-4825","authenticated-orcid":false,"given":"Pablo Daniel","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica M\u00e9dica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain"},{"name":"CIBERER\u2014Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"},{"name":"ITHACA-European Reference Network-Hospital La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","first-page":"e202012121","article-title":"Prevalence of the Phelan-McDermid Syndrome in Spain","volume":"94","author":"Nevado","year":"2020","journal-title":"Rev. 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