Endocrine Abstracts

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Using whole and targeted exome sequencing in individuals from our large, well-phenotyped cohort with self-limited DP, we have identified key candidate genes relevant to the pathogenesis of DP. To date the functional consequences of potentially pathogenic variants identified by our lab in 3 candidate genes have been interrogated via tissue expression studies, in vitro assays and utilising animal models. Our strategy, together with what is known from published literature, has highlighted that the pathogenesis of DP is likely to be heterogenic. Several pathways have been implicated to date, including: abnormalities of GnRH neuronal development and function, GnRH receptor and LH/FSH abnormalities, metabolic and energy homeostasis derangements and transcriptional regulation of the HPG axis.