Endocrine Abstracts

Objectives: Several different pathogenic mechanisms may converge on a final common pathway to produce the phenotype of delayed pubertal timing. Abnormal pubertal timing affects >4% of adolescents and is associated with adverse health outcomes. Up to 80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority the neuroendocrine pathophysiology and genetic regulation remain unclear.

Methods: We have been actively recruiting a UK cohort of patients with severely delayed pubertal onset, or arrested puberty, since 2013. To date, 32 probands and 18 family members DNA have been collected. We have performed next generation sequencing (NGS) - either whole exome sequencing (WES) or whole genome sequencing (WGS) in 20 probands and 4 relatives from this UK self-limited DP patient cohort. The data returned was filtered for genes with rare, predicted deleterious variants that segregated with trait within families with potential biological relevance for delayed puberty.

Results: To date, NGS has been carried out in 48% of the collected cohort (n=24, probands =20, family members =4). A definitive pathogenic mutation has been identified in 18% of those sequenced. Notable mutations include a known homozygous mutation in the GnRH receptor GNRHR, a known homozygous mutation in the gene encoding Neurokinin B, TAC3, a novel heterozygous mutation in FGFR1 and several other potentially pathogenic variants in relevant genes and pathways, including SEMA3E and CCDC141.

Conclusions: The clinical diagnostic distinction between hypogonadotropic hypogonadism and self-limited DP in adolescence is often a difficult one to make. In some cases, identification of definitive genetic mutations can be very informative for management and future planning. These genetic diagnoses also inform our understanding of biology of absent and delayed puberty. There remains uncertainty about the clinical significance of many of the potentially pathogenic variants identified by NGS. This is likely to improve with better knowledge of NGS interpretation, but despite this a definitive genetic diagnosis may not be possible in all patients.