{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T17:01:19Z","timestamp":1773680479776,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RC-000234\/22"],"award-info":[{"award-number":["RC-000234\/22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study describes two siblings from consanguineous parents who exhibit intellectual disability, microcephaly, photosensitivity, bilateral sensorineural hearing loss, numerous freckles, and other clinical features that suggest a potential disruption of the nucleotide excision repair (NER) pathway. Whole exome sequencing (WES) identified a novel homozygous missense variant in the ERCC4 gene, which was predicted to be pathogenic. However, a subsequent peculiar audiometric finding prompted further investigation, revealing a homozygous deletion in the OTOA gene linked to neurosensorial hearing loss. Both variants were located within a run of homozygosity (ROH) on chromosome 16p13.12-p12.2, implicating a complex genetic basis for the observed phenotype. While this study reports a potentially novel ERCC4 variant, it underscores the importance of comprehensive analysis and deep phenotyping in WES data to improve diagnostic accuracy. Our findings advocate for an expanded approach in WES analysis, ensuring more precise diagnoses and improved genetic counseling, particularly when specialized tests for structural variant analysis are unavailable.<\/jats:p>","DOI":"10.3390\/ijms252413471","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T06:48:39Z","timestamp":1734331719000},"page":"13471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling Secondary Mutations in Blended Phenotypes: Dual ERCC4 and OTOA Pathogenic Variants Through WES Analysis"],"prefix":"10.3390","volume":"25","author":[{"given":"Pinella","family":"Failla","sequence":"first","affiliation":[{"name":"Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Saccuzzo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Clinical Biochemistry and Medical Genetics, University of Catania, via Santa Sofia, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7877-938X","authenticated-orcid":false,"given":"Ornella","family":"Galesi","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donatella","family":"Greco","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-6981","authenticated-orcid":false,"given":"Vincenza","family":"Barresi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Clinical Biochemistry and Medical Genetics, University of Catania, via Santa Sofia, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvestra","family":"Amata","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-0683","authenticated-orcid":false,"given":"Corrado","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Clinical Biochemistry and Medical Genetics, University of Catania, via Santa Sofia, 95123 Catania, Italy"},{"name":"Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-6880","authenticated-orcid":false,"given":"Marco","family":"Fichera","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Clinical Biochemistry and Medical Genetics, University of Catania, via Santa Sofia, 95123 Catania, Italy"},{"name":"Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. 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