Identification of a Novel LHCGR Gene Mutation in a Pedigree for Premature Ovarian Failure Among Female Athletes Based on Whole-Exome Sequencing

Abstract

Objective: To identify the genetic mutation responsible for premature ovarian failure in a pedigree, specifically targeting a pair of monozygotic twin sisters who are competitive athletes, using whole-exome sequencing. Design: Whole-exome sequencing analysis. Setting: Advanced Sports Medicine and Reproductive Genetics Center. Intervention: None. Participants: A pair of monozygotic twin sisters with a history of premature ovarian failure, both of whom are professional athletes, along with their family pedigree; a control group consisted of 50 healthy athletes. Main Outcome Measures: High-throughput sequencing technology was utilized to perform whole-exome screening of the proband genes. Sanger sequencing was subsequently conducted on other family members and on the athletes in the control group to confirm the findings. Results: The sequencing identified a heterozygous missense mutation c.1627T>C (p.C543R) in exon 11 of the luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) gene in the proband. This mutation was also present in other affected family members but absent in healthy relatives and the control group of athletes. This mutation has not been previously reported in major genomic databases such as the 1000 Genomes Project or the ExAC.

Conclusions: The c.1627T>C heterozygous mutation in the LHCGR gene likely contributes to the pathogenesis of premature ovarian failure. This finding is particularly significant for the management and genetic counseling of female athletes, offering insights into potential risks and interventions for those predisposed to reproductive health issues.