Endocrine Abstracts

Gonadotropin-releasing hormone (GnRH) is the master hormone regulating the reproductive axis and its pulsatile secretion is crucial for puberty onset and fertility. Disruption in GnRH neuron development or hypothalamic function can lead to absent or delayed puberty (DP) due to GnRH deficiency, with a phenotypic spectrum from severe delayed puberty to partial or complete Hypogonadotropic Hypogonadism (HH). HH can also be present as a shared trait with other neurodevelopmental disorders (NDDs). Mutations in the gene (BRINP2) have been previously associated with NDDs such as autistic spectrum disorder (ASD). BRINP2 is localised to the olfactory bulb, a key site during GnRH neuron migration. The aim of our study was to identify novel genetic aetiology of severe DP by screening and identifying variants in associated genes in our cohort of patients; and ascertain the functional effects of identified variants of interest. Whole exome sequencing (WES) was performed on DNA samples from 180 probands with DP from our patient cohorts to identify potentially pathogenic novel, or rare coding variants in relevant gene pathways. Integrative analysis was performed on genomic data from human patients combined with transcriptomics analysis of rodent immortalized and primary GnRH neurons to determine novel regulators of GnRH neuronal development and function. BRINP2 was identified as a candidate gene of interest as it was found to be significantly upregulated during GnRH neuronal development in these single cell transcriptomics analyses. WES analysis identified three variants in BRINP2 (p.R726W, p.R649Q, p.I629V) in four unrelated probands with severely DP or partial HH, in combination with ASD or other NDD features. These three variants are all rare or ultra-rare and are predicted to be pathogenic by in silico tools. Protein expression of the three mutants was comparable to the reference protein.