EP1343 - ECE_3558 - Rare 5′-UTR variants creating new upstream open reading frames provide a potential novel genetic mechanism in congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder with numerous genes implicated in its pathogenesis. To date, most studies have focused on the coding regions of the genome, leaving ~50% of the CHH genetically unsolved. While the impact of non-coding regions in disease pathogenesis has recently emerged, the role of non-coding variants affecting upstream open reading frames (uORFs) within the 5′ untranslated regions (5′-UTRs), which are known to suppress downstream translation, has not been thoroughly studied. In this study, we aimed: (i) to assess whether patients with CHH are enriched for rare 5′-UTR variants creating new uORFs, and thus having the potential to suppress downstream translation of known CHH genes compared to reproductively normal controls, (ii) to phenotypically characterize CHH individuals harboring such 5′-UTR variants. Whole exome sequencing data of 1403 CHH subjects and 7999 reproductively normal controls from the Mass General Brigham Biobank (MGBB) was analyzed using the GATK pipeline to identify rare 5′UTR variants [minor allele frequency (MAF) <0.1% in autosomal dominant genes and <1% in autosomal and X-linked recessive genes] in 82 known CHH genes. The variants' functional effect was assessed using the UTRannotator, a VEP plugin that identifies variants disrupting existing or creating new uORFs. We detected 50 5′-UTR variants (MAF<1%) with a predicted effect in 30 genes. Such variants were more common in CHH vs controls (1.3% vs 0.7%, P = .034). Variants creating new uORFs were also more common in CHH probands (CHH 0.8%—Controls 0.3%, P = .0159), and this pertained to autosomal dominant genes (P = .06) but not to autosomal and X-linked recessive (P = .114). Variants disrupting existing uORFs were equally prevalent in CHH and Controls (0.5% vs 0.4%, P = ns). Of the 11 CHH probands harboring variants creating new uORFs 6 were males and 5 females; 7 had anosmia (Kallmann syndrome) and 4 normosmic CHH; and 4 had additional non-reproductive characteristics (eg, clinodactyly, short metacarpal, learning disability/speech impairment, amblyopia, ptosis, strabismus). CHH cases are enriched for rare 5′UTR variants that create new uORFs in autosomal dominant genes compared to controls, underscoring the emerging role of non-coding variants in the genetic background of CHH.