{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:49:56Z","timestamp":1792788596655,"version":"4.5.0"},"reference-count":28,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Gabriella Miller Kids First program","award":["X01HL132384"],"award-info":[{"award-number":["X01HL132384"]}],"id":[{"id":"https:\/\/ror.org\/00t76qa96","id-type":"ROR","asserted-by":"crossref"}]},{"name":"DSD-Translational Research network","award":["RO1HD093450"],"award-info":[{"award-number":["RO1HD093450"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder characterized by absent or delayed puberty and infertility due to gonadotropin-releasing hormone deficiency. While loss-of-function variants in FGFR1 are the most commonly known genetic cause of CHH, diagnostic screening typically focuses on coding exons, potentially overlooking pathogenic variants in noncoding regions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated 4 unrelated families with CHH. Family 1 included a mother and 3 daughters presenting with variable reproductive phenotypes and incomplete penetrance of anosmia; Family 3 consisted of a girl with CHH and anosmia; and Families 2 and 4 consisted of male patients who presented with CHH and anosmia. Genetic investigations were done using either exome or genome sequencing. Experimental characterization of the identified intronic variants was conducted using RNA extracted from peripheral blood mononuclear cells. Exome or genome sequencing\u2013based haplotyping was performed for the recurring variant.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In Families 1 to 3, we identified a recurring heterozygous intronic variant in FGFR1: c.92-19G &amp;gt; A. RNA analysis confirmed that this variant generates a cryptic splice acceptor site, leading to the inclusion of 17 intronic nucleotides, resulting in a premature stop codon. Haplotype analysis revealed the variant occurred independently in each family. In Family 4, a distinct heterozygous intronic variant was identified in FGFR1, which was shown to cause intron 15 retention with premature termination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that intronic variants in FGFR1 are a possible cause of CHH and can lead to diverse clinical phenotypes ranging from normosmic CHH to severe Kallmann syndrome, including significant presentation in female patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jendso\/bvag234","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:50:13Z","timestamp":1791373813000},"source":"Crossref","is-referenced-by-count":0,"title":["Recurring and isolated intronic\n                    <i>FGFR1<\/i>\n                    variants as an underdiagnosed cause of congenital hypogonadotropic hypogonadism"],"prefix":"10.1210","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9208-8160","authenticated-orcid":false,"given":"Michal","family":"Yacobi-Bach","sequence":"first","affiliation":[{"name":"The Genetics Institute and Genomics Center, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 ,","place":["Israel"]},{"name":"Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rona","family":"Hagin","sequence":"additional","affiliation":[{"name":"The Genetics Institute and Genomics Center, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bar","family":"Levy Lando","sequence":"additional","affiliation":[{"name":"The Genetics Institute and Genomics Center, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 ,","place":["Israel"]},{"name":"The Gray Faculty of Medical & Health Sciences, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3541-3190","authenticated-orcid":false,"given":"Emmanu\u00e8le","family":"D\u00e9lot","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Science, University of California , Irvine, CA 92697 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5557-3709","authenticated-orcid":false,"given":"Eric","family":"Vilain","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Science, University of California , Irvine, CA 92697 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Center, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 ,","place":["Israel"]},{"name":"The Gray Faculty of Medical & Health Sciences, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6118-696X","authenticated-orcid":false,"given":"Tadeusz","family":"Ka\u0142u\u017cewski","sequence":"additional","affiliation":[{"name":"Department of Genetics, Polish Mother's Memorial Hospital Research Institute , \u0141\u00f3d\u017a 93-338 ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Gach","sequence":"additional","affiliation":[{"name":"Department of Genetics, Polish Mother's Memorial Hospital Research Institute , \u0141\u00f3d\u017a 93-338 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Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilan M","family":"Rutter","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, OH 45229 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-0574","authenticated-orcid":false,"given":"Yael","family":"Lebenthal","sequence":"additional","affiliation":[{"name":"The Gray Faculty of Medical & Health Sciences, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]},{"name":"The Institute of Pediatric Endocrinology, Diabetes and Metabolism, Dana-Dwek Children's Hospital, Tel Aviv Sourasky University Medical Center , Tel Aviv 6423906 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