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SPRY4 – Kallmann Syndrome

Heterozygous variants in SPRY4 have been implicated in Kallmann syndrome (Kallmann syndrome), a form of hypogonadotropic hypogonadism with anosmia. A single 25-year-old man with congenital severe hyposmia and adult-onset isolated hypogonadotropic hypogonadism harbored c.158G>A (p.Arg53Gln) in SPRY4, establishing initial gene-disease correlation (PMID:31781046). In a cohort of 386 unrelated individuals with congenital hypogonadotropic hypogonadism (including KS), targeted sequencing identified SPRY4 variants in 14 additional probands, including c.230C>T (p.Thr77Met), but without clear familial segregation (PMID:23643382) and with incomplete penetrance in one family co-harboring PROKR2 variants (PMID:40034250).

Functional characterization of a KS-associated SPRY4 p.Ser241Tyr mutant demonstrated gain-of-function inhibition of FGF-induced ERK signaling and reduced fibroblast and osteosarcoma cell migration and proliferation, consistent with impaired GnRH neuron development (PMID:33670044). Overall, SPRY4 meets a Limited ClinGen clinical validity classification: 15 probands across multiple reports, absence of definitive segregation, but Moderate functional support for a pathogenic mechanism via enhanced negative regulation of FGF signaling. Key Take-home: SPRY4 variants may act as low-penetrance AD contributors to Kallmann syndrome and warrant inclusion in genetic testing panels with counseling on incomplete penetrance.

References

  • Frontiers in Endocrinology • 2019 • A Rare SPRY4 Gene Mutation Is Associated With Anosmia and Adult-Onset Isolated Hypogonadotropic Hypogonadism. PMID:31781046
  • American Journal of Human Genetics • 2013 • Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. PMID:23643382
  • Global Medical Genetics • 2025 • PROKR2 mutations and SPRY4 variants with uncertain significance in a Kallmann syndrome family: Incomplete penetrance. PMID:40034250
  • International Journal of Molecular Sciences • 2021 • A Sprouty4 Mutation Identified in Kallmann Syndrome Increases the Inhibitory Potency of the Protein towards FGF and Connected Processes. PMID:33670044

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

15 probands (14 from cohort and one case report) with heterozygous SPRY4 variants; no multi-family segregation; supportive functional data

Genetic Evidence

Limited

Heterozygous SPRY4 variants identified in 15 unrelated KS and CHH probands with no segregation

Functional Evidence

Moderate

Cell signaling assays of p.Ser241Tyr SPRY4 show gain-of-function inhibition of FGF signaling consistent with KS phenotype ([PMID:33670044])