Evaluation of risk factors and a gene panel as a tool for unexplained infertility diagnosis by next-generation sequencing

Abstract

Background and Objective: Unexplained infertility is a major challenge in reproductive medicine and requires advanced diagnostic approaches to identify the underlyingfactors accurately. This study aims to evaluate the utility of risk factor analysis and a genepanel in diagnosing unexplained infertility using the next-generation sequencing (NGS)technology. Our study aimed to characterize and identify risk and genetic factors associatedwith unexplained infertility. Materials and methods: A cohort of patients with unexplainedinfertility was comprehensively screened for risk factors and genetic variations using atargeted gene panel (10 couples with unexplained infertility (UI) and 36 fertile couples).108 articles were selected (58 on female infertility and 50 on male infertility) presentinggenes that may be associated with unexplained infertility. A gene panel for unexplainedinfertility was compiled based on the literature data. A customized virtual panel wascreated from the exome sequencing data. Results: In the female group, controls had a highermean age, while in the male patients, both groups were similar in terms of age. Both gendergroups had comparable BMI values. No significant associations (p > 0.05) between riskfactors and unexplained infertility were found when evaluating anthropometric parameters and other sociodemographic characteristics. In two male patients (20%), a moleculardefect was detected in NGS variants classified aspossible benign and probably benignIn particular, missense variants were identified in the UGT2B7 and CATSPER2 genes, Amolecular defect classified as probably damaging was found in five female patients (50%).In particular, missense variants were identified in the CAPN10, MLH3, HABP2, IRS1, GDF9,and SLC19A1 genes. Conclusions: The study emphasizes that unexplained infertility is oftenrelated to mechanisms beyond causative mutations and highlights the need for integrativegenomic research involving broader gene panels and multi-faceted approaches, includingtranscriptomics and epigenetics, to uncover latent genetic predispositions.