FGF17 – Kallmann syndrome

FGF17 (HGNC:3673) has been sequenced in large cohorts of patients with Kallmann syndrome (MONDO:0018800), revealing heterozygous variants in unrelated probands. In a study of 386 CHH/KS individuals, 3 probands carried FGF17 variants including c.560A>G (p.Asn187Ser) (PMID:23643382). A Chinese IHH series identified one heterozygous FGF17 variant among five KS patients (PMID:37799300), and a cohort of 145 IHH probands harbored three novel FGF17 mutations (p.Ile48_Val52del, p.Pro120Leu, and p.Lys191Arg) in KS or nIHH cases (PMID:31748124). All FGF17 variants were rare, predicted deleterious, and found in the heterozygous state, supporting an autosomal dominant or oligogenic inheritance pattern. Across these studies, 7 unrelated KS probands carry FGF17 variants with no available familial segregation data.

Functional analysis of Fgf17(-/-) mice demonstrates midbrain, cerebellar, olfactory bulb, and auditory midbrain patterning defects and altered sound-evoked responses, indicating a developmental role of FGF17 in neural structures (PMID:21356319). However, direct assessment of GnRH neuron migration or olfactory nerve development in these models is lacking. A recent case series reported an FGF17 VUS (p.Gly70Arg) in a cHH patient without functional impact in silico, suggesting some variants may be benign (PMID:37108593). In summary, heterozygous FGF17 variants have been observed in KS cohorts but lack segregation and reproductive functional studies. Key take-home: FGF17 may contribute to Kallmann syndrome in an oligogenic context, but further genetic and mechanistic evidence is required to establish definitive causality.

References

• American journal of human genetics • 2013 • Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. PMID:23643382
• International journal of general medicine • 2023 • Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism. PMID:37799300
• Fertility and sterility • 2020 • Genotypic and phenotypic spectra of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism. PMID:31748124
• NeuroImage • 2011 • Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI. PMID:21356319
• International journal of molecular sciences • 2023 • Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series. PMID:37108593

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