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Fibroblast growth factor receptor 1 (FGFR1) is a tyrosine kinase receptor critical for gonadotropin-releasing hormone (GnRH) neuron development and migration. Heterozygous loss-of-function variants in FGFR1 cause autosomal dominant hypogonadotropic hypogonadism, manifesting as delayed puberty, infertility, and anosmia in Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism (MONDO:0018555).
Genetic evidence for FGFR1 involvement includes multiple case reports identifying de novo or inherited frameshift and nonsense variants. A Japanese family demonstrated germline mosaicism for a somatic 2-bp deletion in exon 10 of FGFR1 in the mother and transmission to her son with hypogonadotropic hypogonadism and dental agenesis (PMID:16418210). Novel truncating variants such as c.246_247del (p.Glu84GlyfsTer26) were reported in a 44-year-old female with hypogonadotropic hypogonadism (PMID:24776628), and other rare missense alleles (e.g., p.Asp476Glu, p.Gly97Ser) have been described in single‐patient normosmic IHH cases (PMID:25501157, PMID:35277108).
Large cohorts confirm FGFR1 variants in 7–10% of idiopathic HH/nIHH patients. Sequencing of 134 normosmic IHH subjects identified heterozygous FGFR1 mutations in nine individuals, all exhibiting impaired receptor function in vitro (PMID:19820032). Targeted panel and exome studies across independent families (totaling 29 probands) reinforce autosomal dominant inheritance with occasional oligogenic interactions, and demonstrate reduced penetrance and variable expressivity.
The variant spectrum spans loss-of-function alleles—nonsense (e.g., c.1864C>T (p.Arg622Ter) (PMID:32853167)), frameshift, and splice site changes—and missense substitutions clustering in the kinase and extracellular domains. Recurrent and de novo mutations underscore a haploinsufficiency mechanism. Reported variant: c.246_247del (p.Glu84GlyfsTer26) (PMID:24776628).
Functional assays demonstrate that FGFR1 missense and truncating variants impair FGF8–FGFR1 signaling, reduce cell surface expression, and diminish kinase activity. In vitro studies in HEK293 and BaF3 cells, as well as zebrafish fgfr1 knock-down models, corroborate loss-of-function and recapitulate GnRH neuron deficits (PMID:32485746; PMID:15221377). Anosmin-1 co-ligand studies further reveal heparan sulfate–dependent modulation of FGFR1 signaling, linking X-linked and autosomal forms of Kallmann syndrome (PMID:15548653).
No published studies dispute FGFR1’s role in hypogonadotropic hypogonadism. The accumulating genetic and functional data—spanning >16 years, >29 probands, multi-family segregation, and concordant loss-of-function assays—support a Definitive gene–disease relationship. FGFR1 testing provides actionable diagnostic and genetic counseling information for patients with IHH/KS.
Gene–Disease AssociationDefinitiveOver 29 unrelated probands across 16 years, multi-family segregation and concordant LOF functional studies Genetic EvidenceStrong29 probands with FGFR1 variants across multiple cohorts; including 6 loss-of-function and 7 missense alleles; reached genetic evidence cap Functional EvidenceModerateMultiple in vitro assays demonstrate loss-of-function; animal models confirm essential role in GnRH neuron development |