{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:27:11Z","timestamp":1788809231084,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"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>Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50\u201360% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia\/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 \u00b1 7.72 years) with suspected or diagnosed HH\/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and\/or KS (FGFR1, PROK2, TAC3R, DCC, WDR11, IL17RD, DUSP6, KAL1, FGF8, IL17RD and DCC). The variant in TAC3R (p.Trp275Ter) was pathogenic; variants in ANOS1 (c.541+1G&gt;A), IL17RD (c.1303_1304dup, p.Lys436ThrfsTer58), and TAC3R (p.Lys361Ter) were likely pathogenic. Nine variants were classified as variants of uncertain significance (VUS). Our study identified a possible genetic cause in 71% of the CHH\/KS cohort, emphasizing the importance of genetic screening and functional characterization of genetic variants in patients with a phenotypically and genetically heterogeneous disorder like CHH.<\/jats:p>","DOI":"10.3390\/ijms26115207","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T12:28:42Z","timestamp":1748435322000},"page":"5207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Novel Genetic Variants in a Cohort of Congenital Hypogonadotropic Hypogonadism: Computational Analysis of Pathogenicity Predictions"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3267-5631","authenticated-orcid":false,"given":"Paola","family":"Chiarello","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Dulbecco Azienda Ospedaliero-Universitaria of Catanzaro, 88100 Catanzaro, Italy"},{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-8272","authenticated-orcid":false,"given":"Gianmarco","family":"Gualtieri","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1831-0324","authenticated-orcid":false,"given":"Sabrina","family":"Bossio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Seminara","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Molinaro","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Antonucci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-0919","authenticated-orcid":false,"given":"Anna","family":"Perri","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8331-5723","authenticated-orcid":false,"given":"Valentina","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4599-8487","authenticated-orcid":false,"given":"Rossella","family":"Cannarella","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-2372","authenticated-orcid":false,"given":"Sandro","family":"La Vignera","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-335X","authenticated-orcid":false,"given":"Aldo E.","family":"Calogero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela A.","family":"Greco","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Economiche, Psicologiche, della Comunicazione, della Formazione e Motorie, Nicol\u00f2 Cusano University, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-7402","authenticated-orcid":false,"given":"Rodolfo","family":"Iuliano","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-358X","authenticated-orcid":false,"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science srl, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-2618","authenticated-orcid":false,"given":"Antonio","family":"Aversa","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Universit\u00e0 degli Studi Magna Gr\u00e6cia di Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1111\/cen.14578","article-title":"Interpretation of Reproductive Hormones before, during and after the Pubertal Transition-Identifying Health and Disordered Puberty","volume":"95","author":"Howard","year":"2021","journal-title":"Clin. 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