FLRT3 and Congenital Hypogonadotropic Hypogonadism

Recent multi‑patient studies have identified rare FLRT3 coding variants in individuals diagnosed with congenital hypogonadotropic hypogonadism (CHH) (PMID:23643382). In one study, FLRT3 variants, including the coding change c.1016A>G (p.Lys339Arg), were observed in 3 unrelated CHH patients (PMID:23643382). Although the total number of affected probands remains modest and segregation analysis is limited, these observations suggest that FLRT3 may act as a contributor within an oligogenic framework in CHH. In addition, a Brazilian cohort study further supported the involvement of several CHH‑associated genes, including FLRT3, though these findings await additional replication.

Supporting the clinical genetic findings, functional studies have demonstrated that FLRT3 plays key roles in neuronal cell adhesion and synapse development – processes that are critical for neuroendocrine function (PMID:22405201). While direct functional assays using CHH patient material are currently lacking, the mechanistic insights provided by these in vitro studies offer biological plausibility for FLRT3’s contribution to CHH pathogenesis. Key take‑home: Although the current genetic evidence for FLRT3 in CHH is limited, its established role in neuronal development underscores its potential clinical utility as a candidate for further diagnostic evaluation.

References

• European journal of endocrinology • 2019 • New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism PMID:31200363
• American journal of human genetics • 2013 • Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism PMID:23643382
• Neuron • 2012 • FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development PMID:22405201

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