SUN-160 Familial Hypogonadotropic Hypogonadism Linked to a Novel Pathogenic Intronic Variant in FGFR1 Gene

Abstract Disclosure: M. Yacobi Bach: None. A. Kurolap: None. R. Hagin: None. S. Shaklai: None. Y. Lebenthal: None. A. Botvinik: None. H. Baris Feldman: None. Y. Greenman: None. Objectives:Hypogonadotropic hypogonadism (HH) is a rare endocrine disorder caused by insufficient secretion of gonadotropin-releasing hormone (GnRH), leading to delayed puberty, gonadal dysfunction, and infertility. Over 20 genes have been implicated in its pathogenesis, including FGFR1. Autosomal dominant variants in FGFR1 can cause either Kallmann syndrome or isolated HH with variable clinical features. We describe a two-generation familial case of HH in a Bukharan Jewish family, caused by a novel intronic FGFR1 variant.Methods: We performed exome sequencing (ES) in a mother and three daughters, diagnosed with HH. RNA was extracted from patient peripheral blood mononuclear cells, and analyzed to study the candidate variant's effect on normal gene splicing. Results: ES of all affected members identified a novel intronic variant in FGFR1 (NM_023110.3): c.92-19G>A. The variant was absent from population databases and previously classified as a variant of unknown significance. In silico splice predictions suggested disruption of canonical splicing, with a SpliceAI score of 0.97. RNA studies confirmed aberrant splicing, revealing that the variant creates a cryptic acceptor site, leading to inclusion of an intronic sequence into exon 3. This results in a frameshift and a premature stop codon.Conclusions:This case highlights the importance of non-coding regions in disease pathogenesis and demonstrates how comprehensive studies can uncover pathogenic mechanisms in rare familial disorders, such as HH. Presentation: Sunday, July 13, 2025