A familial case of Kallmann syndrome: novel variants in ANOS1 and GNRHR genes.

Kallmann syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia, stemming from the defective migration of GnRH and olfactory neurons during embryogenesis. This study investigated a multigenerational family with KS, identifying novel mutations in the ANOS1 (c.78_108del, X-linked) and GNRHR (c.974del, autosomal recessive) genes through genetic testing. Affected males carrying the ANOS1 mutations displayed a range of phenotypes, all of which were associated with hypogonadism and varying degrees of anosmia. Furthermore, isolated mutations in the GNRHR gene were linked to milder forms of hypogonadism. Individuals possessing mutations in both genes exhibited more severe phenotypes, suggesting a digenic mode of inheritance. These findings broaden the known mutational landscape of KS, illustrating how variations and combinations of mutations in multiple genes can lead to diverse symptoms and levels of severity within the same disorder. By integrating clinical and genetic data, this research enhances understanding of the intricate mechanisms underlying KS, highlighting the value of next-generation sequencing in revealing oligogenic contributions to endocrine disorders for improved diagnostics, management, and genetic counseling.