Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome

Alexandra Poch; Michael P Dougherty; Robert A Roman; Lynn Chorich; Zoe Hawkins; Soo-Hyun Kim; Hyung-Goo Kim; Lawrence C Layman

doi:10.1016/j.mce.2024.112224

Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome

Mol Cell Endocrinol. 2024 Apr 7:589:112224. doi: 10.1016/j.mce.2024.112224. Online ahead of print.

Authors

Alexandra Poch¹, Michael P Dougherty², Robert A Roman², Lynn Chorich², Zoe Hawkins², Soo-Hyun Kim³, Hyung-Goo Kim⁴, Lawrence C Layman⁵

Affiliations

¹ Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA. Electronic address: alexandra.m.poch@gmail.com.
² Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
³ Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom.
⁴ Neurological Disorders Research Center, Qatar Biomedical Research Center, Hamad Bin Khalifa University, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁵ Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA; Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, USA.

PMID: 38593951
DOI: 10.1016/j.mce.2024.112224

Abstract

Background: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro.

Hypothesis: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported.

Design: Cross-sectional study.

Setting: University Research Laboratory.

Subjects: 158 patients with nHH/KS.

Methods: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing.

Main outcome measures: P/LP variants in nHH/KS genes.

Results: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant.

Conclusion: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Keywords: Digenic; Idiopathic hypogonadotropic hypogonadism; Kallmann Syndrome; Molecular genetics.

Published by Elsevier B.V.