SUN-162 The Contribution Of Rare Non-coding 5’UTR Variants In The Genetic Architecture Of Isolated Hypogonadotropic Hypogonadism

Abstract Disclosure: G. Markantes: None. J. Fu: None. M.B. Campbell: None. H. Brand: None. M. Talkowski: None. L. Plummer: None. S.B. Seminara: None. R. Balasubramanian: None. M.I. Stamou: None. Introduction: Isolated hypogonadotropic hypogonadism (IHH) is a rare heritable disease caused by GnRH deficiency leading to pubertal failure and infertility. Despite current strategies, ∼50% of the genetic etiology of IHH remains unknown. Part of the “missing heritability” could be explained by variation in the non-coding regulatory regions of the genome. Among those variants, non-coding variants in the 5’ untranslated regions (5’UTR) of the genome are known to regulate translation of protein coding genes via multiple mechanisms including changes in the upstream open reading frames (uORFs) of the coding genes. In this study, we hypothesized that patients with IHH will be enriched for rare 5’UTR variants in IHH genes compared to reproductively normal controls. Methods: Whole exome sequencing datasets from 1,403 IHH probands (cases) with 7,999 reproductively normal controls from the Mass General Brigham Biobank (MGBB) were joint-called and analyzed with the GATK pipeline. WES data was analyzed for rare variants in the 5’UTR regions of 102 previously associated with IHH genes. Rarity of the variants was evaluated based on their minor allele frequency (MAF) and their functional effect was investigated with the utilization of the UTRannotator, a VEP plugin that identifies variants disrupting existing or creating new uORFs. Results: We detected a total of 1,182 5’-UTR variants with a MAF <0.1%. Thirty-seven probands harbored rare 5’UTR variants, that created a new uORF or disrupted an existing uORF, compared to 126 reproductively healthy controls (2.6% of the cases vs. 1.5% of the controls, p value = 0.0075). Twenty-four were males and 13 were females. The probands with the rare 5’UTR variants were diagnosed with IHH with anosmia (i.e., Kallmann syndrome, N=18) and normosmic IHH (N=19). The genes with the highest enrichment of such rare 5’UTR variants were SEMA3A (p=0.0022), TBC1D20 (p=0.0022) and FLRT3 (0.0033). Conclusions: The IHH cohort was enriched for rare 5’UTR variants that created a new or disrupted an existing uORF of IHH genes compared to reproductively normal controls. These data highlight the previously unappreciated role of non-coding variants in the genetic architecture of IHH. Presentation: Sunday, July 13, 2025