Endocrine Abstracts

Self-limited delayed puberty (SLDP) is characterized by an onset of puberty that is more than 2-2.5 standard deviations later than the population mean age and is often familial with strong genetic determinants. The reproductive axis is regulated by gonadotropin-releasing hormone (GnRH), which plays a crucial role in initiating puberty and maintaining fertility through its pulsatile secretion. Disruption in GnRH neuron development or hypothalamic function can lead to delayed puberty (DP). UK Biobank data has identified negative health outcomes associated with SLDP including early menopause/andropause and cognitive and psychosocial disabilities. Consequently, there has been extensive research to investigate genes affecting the hypothalamic-pituitary-gonadal (HPG) axis that might be implicated in the pathogenesis of DP by our group and others which has identified sequence variation contributing to the aetiology of SLDP. However, factors beyond nucleotide variations, such as epigenetic changes and CNVs can also lead to pubertal timing disorders. Moreover, CNVs are seen in multiple individuals (n=92) from the Deciphering Developmental Disorders study (https://www.deciphergenomics.org) with a phenotype including DP (HP:0000823). We performed whole genome sequencing on 49 probands with SLDP and subsequently, analysed the data for CNV. The data was initially called, annotated, filtered then partitioned for classification of CNVs using a command-line tool that implements the American College of Medical Genetics and Genomics (ACMG) guidelines to evaluate the pathogenicity of germline duplications and deletions. Using an unbiased candidate gene approach, we identified several deletions that affected 60 known/predicted dosage sensitive genes combined with functional enrichment analysis. This revealed potential molecular pathways involved in the pathogenesis of SLDP, including histone acetylation, and neural plate development. This study highlights the role of CNVs in SLDP and expands our understanding of the biological processes involved in this condition, shedding light on the complex mechanisms underlying DP.