ESPE Abstracts (2015) 84 HA1

aBarts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK, bBarts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre for Translational Bioinformatics, Queen Mary University of London, London, UK, cDepartment of Clinical Pharmacology, Barts and The London School of Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK, dNIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK, eDepartment of Life Sciences, Imperial College London, Centre for Integrative Systems Biology and Bioinformatics, London, UK, fChildren’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, gDepartment of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel, hDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy, iUniversity College London (UCL), Institute of Ophthalmology, London, UK

Background: Timing of puberty is associated with height, cardiovascular health and cancer risk, with a significant public health impact. Previous studies estimate that 60–80% 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.

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