FEZF1 – Kallmann syndrome

Mutations in FEZF1 have recently been implicated in the pathogenesis of Kallmann syndrome, a disorder characterized by anosmia and hypogonadotropic hypogonadism. In a landmark study, homozygous loss‑of‑function mutations in FEZF1 were discovered in two independent consanguineous families, where each family contributed two affected siblings (PMID:25192046). This finding emerged from a cohort of 30 individuals with Kallmann syndrome, strengthening the link between FEZF1 disruption and the clinical phenotype.

Genetic evidence supports this association, with multiple distinct variant types being reported. Notably, the variant c.832C>T (p.His278Tyr) was identified, fulfilling current HGVS criteria and providing a clear molecular marker for the disorder. Additional support comes from another independent study which detected a FEZF1 variant in a trigenic pattern in a set of Chinese families with Kallmann syndrome (PMID:32400067). Segregation analysis in these families further bolsters the assertion that FEZF1 mutations contribute to disease causation.

The observed inheritance pattern in these reports is autosomal recessive, which is consistent with the occurrence of homozygous loss‑of‑function changes in affected individuals. Familial segregation data indicate that affected siblings reliably share the pathogenic alleles, thereby reinforcing the genetic linkage between FEZF1 mutations and Kallmann syndrome. The reported evidence includes both missense and frameshift mutations that, when occurring in the homozygous state, lead to consistent clinical manifestations.

Experimental studies underpinning these genetic observations highlight FEZF1’s role in neuronal migration. The FEZF1 protein is essential for allowing olfactory receptor neuron axons to penetrate the central nervous system basal lamina, a mechanism that is critical for the proper migration of gonadotropin‑releasing hormone neurons. Disruption of this process is thought to be the key pathogenic mechanism leading to the clinical features of Kallmann syndrome, thereby linking basic biological function with human disease (PMID:25192046).

Taken together, the convergence of genetic findings and experimental data provides a robust framework for the association of FEZF1 mutations with Kallmann syndrome. While additional genetic factors may also contribute to the heterogeneity of the disorder, FEZF1 represents a critical component in the molecular diagnosis and understanding of the underlying pathophysiology.

Key take‑home: FEZF1 mutation analysis should be integrated into diagnostic panels for Kallmann syndrome as its established role in GnRH neuron migration offers significant clinical utility.

References

• American journal of human genetics • 2014 • Mutations in FEZF1 cause Kallmann syndrome PMID:25192046
• Andrologia • 2020 • Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing PMID:32400067

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