IL17RD – Kallmann syndrome

IL17RD has been implicated as a contributing gene in Kallmann syndrome (Kallmann syndrome) through case, cohort, and functional studies. In a sporadic KS patient, a heterozygous IL17RD variant c.2101G>A (p.Gly701Ser) was identified, inherited from an unaffected mother, and predicted to disrupt fibroblast growth factor signaling (PMID:38628584). In a 2013 cohort of 386 unrelated congenital hypogonadotropic hypogonadism (CHH) individuals, IL17RD mutations were found in 8 KS probands, with in vitro assays demonstrating impaired receptor function and a strong link to hearing loss in 6/8 (PMID:23643382). In a Chinese IHH cohort of 196 patients, 7 carried heterozygous IL17RD variants (including c.572C>T (p.Pro191Leu)), all inherited from unaffected parents, and 4 showed oligogenic inheritance with other CHH genes (PMID:32389901).

Functional studies of IL17RD variants show altered FGF8–FGFR1 pathway signaling consistent with KS pathobiology, but no animal or rescue models have been reported to date. Segregation analyses are limited, with no affected relatives carrying IL17RD variants, suggesting incomplete penetrance or a modifier role. Altogether, IL17RD contributes to KS susceptibility primarily in an oligogenic context; further familial co-segregation and in vivo validation are needed. Key Take-home: IL17RD testing may inform oligogenic diagnostic panels for Kallmann syndrome.

References

• Frontiers in endocrinology • 2024 • Clinical phenotype of a Kallmann syndrome patient with IL17RD and CPEB4 variants PMID:38628584
• American journal of human genetics • 2013 • Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism PMID:23643382
• Journal of medical genetics • 2021 • Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism PMID:32389901

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