{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:31:48Z","timestamp":1784543508491,"version":"3.55.0"},"reference-count":20,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union NextGenerationEU","award":["L4F87B"],"award-info":[{"award-number":["L4F87B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability\/developmental delay (ID\/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (ABCC9, AKT1, AKT2, AKT3, BRWD3, DIS3L2, DNMT3A, EZH2, GPC3, GPC4, HERC1, MED12, MTOR, NFIA, NFIX, NSD1, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PPP2R1A, PPP2R5D, PTEN, RAB39B, RNF135, SETD2, and TBC1D7) because of neurodevelopmental impairment, including ID\/DD, ASD\/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD. Results: Pathogenic variants leading to the diagnosis of monogenic conditions were detected in 22 patients (28%), including NSD1 (2), PTEN (16), and PPP2R5D (4). Distinctive of the PTEN-associated phenotype were true macrocephaly (100%), ASD or behaviour abnormalities (92%), mild\/borderline ID (79%), and no facial dysmorphisms. Typical of the PPP2R5D-associated phenotype were relative macrocephaly (75%), a few unspecific peculiar facial characteristics (50%), and a more variable presentation of the neurodevelopmental phenotype. Conclusions: Pathogenic variants in PTEN and PPP2R5D are the most recurrent gene mutations in a patient-oriented procedure for the genetic diagnosis of apparently idiopathic ASD and behaviour abnormalities associated with macrocephaly. The clinical applicability of the presented diagnostic strategy is discussed.<\/jats:p>","DOI":"10.3390\/genes16040469","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:31:36Z","timestamp":1745181096000},"page":"469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clinical-Genetic Approach to Conditions with Macrocephaly and ASD\/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8017-8050","authenticated-orcid":false,"given":"Federica Francesca","family":"L\u2019Erario","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2171-1563","authenticated-orcid":false,"given":"Annalisa","family":"Gazzellone","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Contaldo","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2267-8077","authenticated-orcid":false,"given":"Chiara","family":"Veredice","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Carapelle","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Gloria","family":"Renzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6518-1700","authenticated-orcid":false,"given":"Clarissa","family":"Modafferi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Palucci","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0640-4923","authenticated-orcid":false,"given":"Pino","family":"D\u2019Ambrosio","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Sonnini","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Loberti","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Panfili","sequence":"additional","affiliation":[{"name":"Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Lucci Cordisco","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5104-1521","authenticated-orcid":false,"given":"Pietro","family":"Chiurazzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Trevisan","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2661-4831","authenticated-orcid":false,"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-9939","authenticated-orcid":false,"given":"Maria Grazia","family":"Pomponi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-8882","authenticated-orcid":false,"given":"Giuseppe","family":"Marangi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1002\/ajmg.a.32434","article-title":"Genetic Disorders Associated with Macrocephaly","volume":"146A","author":"Williams","year":"2008","journal-title":"Am. 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