Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome.

Hexose-6-phosphate dehydrogenase (H6PD) inactivating mutations cause cortisone reductase deficiency, which manifests with hyperandrogenism unexplained by commonly used tests and, thus, mimics polycystic ovary syndrome (PCOS). The aim of this study was to screen for mutations of H6PD gene in PCOS patients with biochemical hyperandrogenemia. Direct DNA sequencing of the entire H6PD coding sequence was performed in 74 PCOS patients and 31 healthy controls. Results were confirmed by PCR-restriction fragment length polymorphism assay to determine the genotypic frequency of the variants. Multiple novel missense variants were detected in the study. Two exon 2 variants (acccaggc deletion proximal to the start codon and D151A) and two exon 5 variants (R453Q and P554L) were common, occurring in 23.8%, 17.1%, 35.2%, and 16.1%, respectively. There was significant linkage disequilibrium between the exon 2 and exon 5 variants. No significant differences were observed in the genotype, allele distributions, or adrenal function tests of the variants between cases and control groups. We did not detect any reported inactivating mutations in our study. Although the H6PD gene is very polymorphic and missense variants are common, coding variants rarely (<1.5%) are responsible for hyperandrogenemic PCOS. We suggest that genetic studies be reserved for patients with dexamethasone-suppressible adrenal hyperandrogenism who have a discrepancy between urinary 17α-hydroxycorticoid and cortisol excretion.