{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T03:54:56Z","timestamp":1769054096578,"version":"3.49.0"},"reference-count":30,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,17]],"date-time":"2022-04-17T00:00:00Z","timestamp":1650153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology","award":["PTDC\/SAU-GMG\/098419\/2008 and UIDB\/00709\/2020"],"award-info":[{"award-number":["PTDC\/SAU-GMG\/098419\/2008 and UIDB\/00709\/2020"]}]},{"name":"Sidra Medicine","award":["SDR400038"],"award-info":[{"award-number":["SDR400038"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive endocrine disorder characterized by complete or partial failure of pubertal development and infertility due to deficiency of the gonadotropin-releasing hormone (GnRH). CHH has a significant clinical heterogeneity and can be caused by mutations in over 30 genes. The aim of this study was to investigate the genetic defect in two siblings with CHH. A woman with CHH associated with anosmia and her brother with normosmic CHH were investigated by whole exome sequencing. The genetic studies revealed a novel heterozygous missense mutation in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene (NM_023110.3: c.242T&gt;C, p.Ile81Thr) in the affected siblings and in their unaffected father. The mutation affected a conserved amino acid within the first Ig-like domain (D1) of the protein, was predicted to be pathogenic by structure and sequence-based prediction methods, and was absent in ethnically matched controls. These were consistent with a critical role for the identified missense mutation in the activity of the FGFR1 protein. In conclusion, our identification of a novel missense mutation of the FGFR1 gene associated with a variable expression and incomplete penetrance of CHH extends the known mutational spectrum of this gene and may contribute to the understanding of the pathogenesis of CHH.<\/jats:p>","DOI":"10.3390\/ijms23084423","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T04:21:28Z","timestamp":1650255688000},"page":"4423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1513-2722","authenticated-orcid":false,"given":"L\u00facia","family":"Fadiga","sequence":"first","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Mariana","family":"Lavrador","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Nuno","family":"Vicente","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"given":"Lu\u00edsa","family":"Barros","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6659-1200","authenticated-orcid":false,"given":"Catarina","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Asma","family":"Al-Naama","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha P.O. Box 26999, Qatar"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-0396","authenticated-orcid":false,"given":"Luis","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Sidra Medicine, Doha P.O. Box 26999, Qatar"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-8900","authenticated-orcid":false,"given":"Manuel","family":"Lemos","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1210\/er.2018-00116","article-title":"Clinical Management of Congenital Hypogonadotropic Hypogonadism","volume":"40","author":"Young","year":"2019","journal-title":"Endocr. 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