{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:48:46Z","timestamp":1760057326287,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene (HNRNPC) have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)\/intellectual disability (ID) is also wide, ranging from mild to severe. The mutational spectrum is relatively broad with exon deletions and splice site and frameshift variants distributed along the entire length of the gene leading to HNRNPC loss of function. Only two missense changes located within the RNA-binding motif (RBM) and adjacent linker region of the more abundant isoform (Arg64Trp and Arg99Gln) have been described. Notably, the Arg99Gln amino acid substitution was reported in a subject presenting with a more complex and unique clinical phenotype characterized by distinctive facial features, DD\/ID, cochlear aplasia, and bilateral colobomatous microphthalmia, suggesting the possible occurrence of phenotypic heterogeneity. Results: Here, we report the second individual carrying the Arg99Gln change in HNRNPC and having clinical features with a significant overlap with the peculiar phenotype of the previously described subject, supporting the occurrence of a genotype\u2013phenotype correlation. Conclusions: Due to the concomitant occurrence of ocular and cochlear involvement as recognizable diagnostic handles, we propose that the HNRNPCArg99Gln-related phenotype should be considered as a potential differential diagnosis in subjects with ID and major signs of CHARGE syndrome not fulfilling the minimum criteria for a clinical diagnosis.<\/jats:p>","DOI":"10.3390\/genes16020176","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:36:32Z","timestamp":1738560992000},"page":"176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Arg99Gln Substitution in HNRNPC Is Associated with a Distinctive Clinical Phenotype Characterized by Facial Dysmorphism and Ocular and Cochlear Anomalies"],"prefix":"10.3390","volume":"16","author":[{"given":"Luigi","family":"Chiriatti","sequence":"first","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4815-9550","authenticated-orcid":false,"given":"Manuela","family":"Priolo","sequence":"additional","affiliation":[{"name":"Medical and Molecular Genetics, AORN A. Cardarelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-6657","authenticated-orcid":false,"given":"Roberta","family":"Onesimo","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4584-0663","authenticated-orcid":false,"given":"Mattia","family":"Carvetta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Biochemical Sciences \u201cAlessandro Rossi Fanelli\u201d, Sapienza University, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-637X","authenticated-orcid":false,"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 A. Gemelli, IRCCS, 00168 Rome, Italy"},{"name":"Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-4998","authenticated-orcid":false,"given":"Alessandro","family":"Bruselles","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Cappelletti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University \u201cTor Vergata\u201d, 00173 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Ferilli","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"},{"name":"Department of Computer, Control and Management Engineering, Sapienza University, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Ricci","sequence":"additional","affiliation":[{"name":"National Centre of Services and Research for Prevention of Blindness and Rehabilitation of Low Vision Patients, IAPB Italia Onlus, 00185 Rome, Italy"},{"name":"Pediatric Neuropsychiatric Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4766-7753","authenticated-orcid":false,"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Ciolfi","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 A. Gemelli, IRCCS, 00168 Rome, Italy"},{"name":"Facolt\u00e0 di Medicina e Chirurgia, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00143 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s00439-016-1683-5","article-title":"The hnRNP family: Insights into their role in health and disease","volume":"135","author":"Geuens","year":"2016","journal-title":"Hum. 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A"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/176\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:25:19Z","timestamp":1760027119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,1]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["genes16020176"],"URL":"https:\/\/doi.org\/10.3390\/genes16020176","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,2,1]]}}}