{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:35:07Z","timestamp":1784126107611,"version":"3.55.0"},"reference-count":59,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T00:00:00Z","timestamp":1686355200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Emma ed Ernesto Rulfo per la Genetica Medica"},{"name":"Lascito Feliciani-Ferretti"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.<\/jats:p>","DOI":"10.3390\/genes14061241","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T01:28:21Z","timestamp":1686533301000},"page":"1241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Success and Pitfalls of Genetic Testing in Undiagnosed Diseases: Whole Exome Sequencing and Beyond"],"prefix":"10.3390","volume":"14","author":[{"given":"Valeria","family":"Barili","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7520-3721","authenticated-orcid":false,"given":"Enrico","family":"Ambrosini","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Uliana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Bellini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neonatology, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Vitetta","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-7031","authenticated-orcid":false,"given":"Davide","family":"Martorana","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6816-6131","authenticated-orcid":false,"given":"Ilenia Rita","family":"Cannizzaro","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta","family":"Taiani","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2104-4016","authenticated-orcid":false,"given":"Erika","family":"De Sensi","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Caggiati","sequence":"additional","affiliation":[{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hilton","sequence":"additional","affiliation":[{"name":"Division of Evolution, Infection & Genomics, School of Biological Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK"},{"name":"Manchester Centre for Genomic Medicine, Saint Mary\u2019s Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth","family":"Banka","sequence":"additional","affiliation":[{"name":"Division of Evolution, Infection & Genomics, School of Biological Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, UK"},{"name":"Manchester Centre for Genomic Medicine, Saint Mary\u2019s Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-6786","authenticated-orcid":false,"given":"Antonio","family":"Percesepe","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"},{"name":"Medical Genetics, University Hospital of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrg3999","article-title":"Genetic Studies in Intellectual Disability and Related Disorders","volume":"17","author":"Vissers","year":"2016","journal-title":"Nat. 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