IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty

Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons invitro, and perturbed migration andextension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP. Synopsis Self-limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans. Pathogenic mutations in IGSF10 are found in patients with self-limited delayed puberty. IGSF10 is a gene of previously unclear function with no known human mutations. IGSF10 is expressed within the nasal mesenchyme during fetal development, in a pattern similar to known chemokines that direct migrational GnRH neurons to the hypothalamus. Knockdown of IGSF10 led to a reduced migration of GnRH neurons invitro and in a transgenic zebrafish model. IGSF10 loss-of-function mutations were also identified in patients with hypothalamic amenorrhea, suggesting an overlapping genetic and mechanistic basis between different types of functional hypogonadotropic hypogonadism, including DP and hypothalamic amenorrhea.