Loss-of-Function Mutations in SEMA3F and gePLXNA3 Encoding Semaphorin-3F and its Receptor Plexin-A3 Respectively Cause Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic condition characterized by absent puberty and infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal (normosmic IHH, nIHH) or compromised olfaction (Kallmann syndrome, KS). Several semaphorins have been shown to be potent modulators of the GnRH, olfactory and vomeronasal system development. Using exome sequencing, we screened 216 IHH patients and identified 10 ultra-rare missense variants in SEMA3F and PLXNA3 in 15 patients, corresponding to 6.9% of our study cohort. Most of these variants are predicted to affect SEMA3F secretion or signaling activity based on predictive algorithms and in vitro functional assays. We also demonstrated the expression of SEMA3F, and of its obligatory holoreceptors, PlexinAs, along the GnRH migratory route in human fetuses. We report that SEMA3F signaling insufficiency contributes to the pathogenesis of IHH.