Disorders of human pubertal timing (360G-Wellcome-222049_Z_20_Z)

My proposal is focused on understanding the genetic basis, and consequently the pathophysiology, underpinning disordered human puberty. Pubertal disorders are common, but associated with severe comorbidities. Delayed puberty presents a diagnostic challenge in adolescence, as conditions of gonadotropin deficiency and isolated delayed puberty display the same clinical and biochemical phenotype. However, correct management is vital because the former is associated with infertility and requires intensive reproductive therapy, whereas the latter is self-limiting but associated with a shortened reproductive lifespan. The biological mechanisms of precocious puberty, a condition associated with increased long-term cardiovascular and cancer risk and thus with significant impact on public health, remain similarly opaque. The identification of causal genetic defects in disordered puberty allows interrogation of the key regulators of human puberty. I will use whole genome sequencing, comparative transcriptomics and methylomics studies in my large human cohort with disordered puberty, to define shared exonic and regulatory mutations resulting in delayed and precocious puberty. I aim to characterise the biological mechanisms underlying pubertal disorders through functional characterisation of novel genomic defects using cellular assays and animal models. These findings will ultimately translate to improved diagnostics, tailored therapeutic management and improved long-term outcomes for patients with disorders of puberty.