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

TL;DR

A family with Kallmann syndrome shows new gene mutations that cause varied symptoms, highlighting the role of multiple genes in the disorder.

Contribution

The study identifies novel mutations in ANOS1 and GNRHR genes and suggests a digenic inheritance pattern in Kallmann syndrome.

Findings

Novel X-linked ANOS1 and autosomal recessive GNRHR mutations were found in a family with Kallmann syndrome.

Individuals with mutations in both genes had more severe symptoms than those with single mutations.

Next-generation sequencing revealed oligogenic contributions to Kallmann syndrome.

Abstract

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.

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