Background: Timing of puberty is associated with height, cardiovascular health and cancer risk, with a significant public health impact. Previous studies estimate that 6080% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) often segregates in an autosomal dominant pattern, but the underlying genetic background is unknown.
Methods: We performed whole exome sequencing in 52 members of 7 families from our patient cohort with self-limited DP, with follow-up targeted re-sequencing of candidate genes in a further 42 families. For one candidate gene we defined tissue expression in human and mouse embryos by in situ hybridization and immunohistochemistry. The effects of gene knockdown were investigated via in vitro neuronal migration assays, and in vivo using a transgenic zebrafish model with fluorescently labelled GnRH neurons.
Results: We identified four rare heterozygous mutations in IGSF10 in 29 members of ten unrelated families. All four variants were in evolutionarily conserved positions and were predicted by in silico analysis to have a deleterious effect on protein function. Statistical tests showed a significant difference in the prevalence of these mutations within DP cases compared to a general population (P=4.46×10−3), and a significant association between these mutations and the delayed puberty trait within our cohort (P=3.47×10-4). IGSF10 mRNA shows strong expression in the nasal mesenchyme in mouse and human embryos, during the time-period when GnRH neurons migrate from their nasal origin towards the hypothalamus. IGSF10 knockdown caused reduced migration of immature GnRH neurons in the in vitro analysis, and perturbed migration and extension of GnRH neurons in the transgenic zebrafish model.
Conclusions: We present our novel finding that IGSF10 mutations contribute to the phenotype of self-limited delayed puberty in humans, at least in part through the mechanism of impaired migration of GnRH neurons during embryonic development.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology