An Investigation of Steroid Biosynthesis Pathway Genes in Women with Polycystic Ovary Syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy whose heterogeneous genetic basis results in a variable clinical presentation. One of the main clinical features of PCOS is hyperandrogenism which occurs due to dysregulation of ovarian and adrenal steroidogenesis. AIMS: This study aimed to investigate potentially pathogenic variants in steroidogenic genes associated with PCOS. SETTINGS AND DESIGN: This was a hospital-based observational study. MATERIALS AND METHODS: We recruited 51 women who presented with PCOS. Fasting blood samples were drawn from the participants and their whole-exome sequencing analysis was carried out to look for pathogenic variants involved in steroidogenic pathways. The variants were predicted for their probable deleterious effects on proteins through in silico prediction tools. We evaluated the variants with respect to the hormonal characteristics and clinical outcomes of the patients. STATISTICAL ANALYSIS USED: All variables were analysed using GraphPad Prism 8. Kruskal–Wallis t-test and Fisher's exact test were used to compare clinical parameters and frequency differences among PCOS patients with and without variants. RESULTS: The data presented here reveal eight heterozygous exonic variants, namely CYP21A2 (p.Ala392Thr, p.Gln319Ter and p.I143N), steroidogenic acute regulatory (p.Arg53 Leu), AKR1C3 (p.Phe205Val), P450 oxidoreductase (p.Val334Ile and p.Val251Met) and HSD17B6 (p.Gly40Ser), of which three were pathogenic, and four variants of uncertain significance in 8 out of 51 patients (15.68%). The identified variants were predicted to cause protein destabilisation, thus likely contributing to the pathogenesis of PCOS. Some of the variants showed significant differences between PCOS patients and population database (P < 0.05). CONCLUSION: The results of this study add to the mutational spectrum of steroidogenic genes and their association with PCOS.