MON-LB048 Delayed or Absent? Use of Next Generation Sequencing Diagnostic Tools in a UK Puberty Cohort

Abstract

Objectives: Several different pathogenic mechanisms may converge on a final common pathway to produce the phenotype of delayed pubertal timing. Late puberty affects 2% of adolescents and is associated with adverse health outcomes. Self-limited delayed puberty (DP) is the commonest diagnosis and familial DP segregates in an autosomal dominant pattern. However, for those adolescents with extreme DP the clinical diagnosis of self-limited DP versus hypogonadotropic hypogonadism (HH) is particularly difficult. This is a critical distinction as the therapies, timeframe of management and follow up are distinct. We hypothesise that the use of next generation sequencing (NGS) tools can assist the clinical management of this group of patients. Methods: We have been actively recruiting a UK cohort of patients with severely delayed pubertal onset, or arrested puberty, since 2013, as part of a National Institute for Health Research Clinical Research Network portfolio. To date, DNA from 60 individuals (41 probands and 19 family members) has been collected. We have performed NGS - either whole exome sequencing (WES) or whole genome sequencing (WGS) - in 22 probands and 6 relatives from this UK 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 DP or HH. Results: To date, NGS has been carried out in 47% of the collected cohort (n=28, probands = 22, family members = 6). A definitive pathogenic mutation has been identified in 29% 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 HS6ST1, SEMA3E and CCDC141. Conclusions: The clinical diagnostic distinction between HH 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. SRH is funded by the NIHR; The Wellcome Trust [102745] and Rosetrees Trust [M222-F1]. MRB and CPC are funded by the NIHR, and this work forms part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.