SUN-155 The Prevalence of Pathogenic Variants in Medically Actionable Genes Among Women with Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome

Abstract Disclosure: J.M. Kwal: None. L.P. Chorich: None. Z. Hawkins: None. L. Grater: None. J. Knight: None. H.S. Taylor: None. L.C. Layman: None. Background: Idiopathic Hypogonadotropic Hypogonadism (IHH) is an endocrine disorder characterized by impaired GnRH neuron migration along olfactory axons (Kallmann syndrome—KS) or defects in the production or action of gonadotropin-releasing hormone (GnRH). This results in low or inappropriately normal serum concentrations of luteinizing hormone and follicle-stimulating hormone and deficient gonadal ѕtеrоiԁs and subsequent infertility. Our group previously showed that other types of infertility are associated with an increased prevalence of pathogenic and likely pathogenic (P/LP) variants in medically actionable genes (MAGs) vs. controls when exome sequencing was performed. Objective: We hypothesize that a diagnosis of IHH/KS could also increase the risk of P/LP variants in these MAGs, which predispose to future medical illness. Methods: Exome sequencing was performed on 144 patients with IHH/KS. We previously sequenced these 144 patients, and 19% of them had P/LP variants in known IHH/KS genes, which was the primary indication for sequencing. In this study we wanted to determine if they had P/LP variants in MAG. Variants were filtered to include only those in the 81 genes from the ACMG SF v3.2 list for secondary findings (i.e., MAGs). Sanger sequencing is being performed to confirm results. The prevalence of these variants was compared to public control data from the UK Biobank and eMERGE databases. Power analysis at an alpha of 0.05 to detect a 4% (or 3-fold) difference in the prevalence of P/LP variants between the IHH/KS cohort and the national databases would require 141 patients at 80% power. Results: We showed that 5/144 (3.5%) individuals with IHH/KS had at least one P/LP variant in 4 MAGs. Of these, 2/144 (1.4%) persons had P/LP variants in cancer-related genes (TSC1); 4/144 (2.8%) had variants in cardiovascular disease genes (SCN5A, MYBPC3), and 1/144 (0.7%) had P/LP variants in inborn errors of metabolism (RYR1). One person, not included, had over 13 variants, which was thought to be artifact. There were two additional people who were heterozygous for HFE. This was not sufficient to cause medical illness since hemochromatosis is autosomal recessive. The prevalence of our variants in MAGs was 1.4-fold higher than in the UK Biobank and 1.8-fold higher than in the eMERGE database when 59 MAGs are included. However, this was not statistically different than the 2.5% and 2% from the UKB and eMERGE control databases. Conclusions: Individuals with IHH/KS had a 3.5% detection rate of P/LP variants in MAG, which did not differ from the prevalence in the general population. These findings suggest that secondary findings in IHH/KS are not a risk factor for genetic causes affecting future medical illness. Presentation: Sunday, July 13, 2025