FGF8 – Hypogonadotropic Hypogonadism

Fibroblast growth factor 8 (FGF8) is a secreted ligand for FGFR1 critical in the ontogenesis of gonadotropin-releasing hormone (GnRH) neurons. Heterozygous loss-of-function and missense variants in FGF8 have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH), with or without anosmia, defining an autosomal dominant mechanism of GnRH deficiency (FGF8; hypogonadotropic hypogonadism).

Clinical Validity

The gene–disease association is classified as Strong: two unrelated probands with heterozygous nonsense variants (p.Arg127Ter, p.Arg129Ter) and six additional probands with distinct missense alleles have been reported; one kindred shows segregation in four additional affected relatives; concordant in vitro and murine model data support haploinsufficiency (6 probands + 2 probands; 4 affected relatives; functional concordance) (PMID:20463092; PMID:18596921).

Genetic Evidence

Inheritance Mode: Autosomal dominant.
Segregation: Four additional affected siblings carrying p.Arg127Ter in one kindred ([PMID:20463092]).
Case Series: Two unrelated probands with nonsense variants; six unrelated probands with heterozygous missense variants affecting all or specific FGF8 isoforms.
Variant Spectrum: 2 nonsense (LoF), 6 missense; no recurrent founder alleles reported; variable olfactory phenotypes (anosmic KS or normosmic IHH).
Key Variant: c.379C>T (p.Arg127Ter) — truncates core domain and abolishes ligand activity ([PMID:20463092]).

Functional Evidence

Mechanism: Haploinsufficiency of FGF8 impairs GnRH neuron fate specification and maintenance.
Assays: Mutant FGF8b/f ligands show reduced signaling in cell‐based assays; mice homozygous for a hypomorphic Fgf8 allele lack GnRH neurons, while heterozygotes have a 50–70% reduction in GnRH neuron number and peptide levels ([PMID:18596921]).

Integration and Clinical Utility

Heterozygous FGF8 variants cause autosomal dominant IHH with variable penetrance, occasionally accompanied by anosmia, cleft lip/palate, hearing impairment, or delayed puberty. Genetic testing for FGF8 should be considered in IHH/Kallmann syndrome diagnostics. Functional data corroborate pathogenicity and support pedigree counseling and potential targeted therapies.

Key Take-home: Heterozygous loss-of-function and missense mutations in FGF8 result in autosomal dominant hypogonadotropic hypogonadism via haploinsufficiency.

References

• The Journal of clinical endocrinology and metabolism | 2010 | Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency PMID:20463092
• The Journal of clinical investigation | 2008 | Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice PMID:18596921

Evidence Based Scoring (AI generated)