Congenital Hypogonadotropic Hypogonadism Caused by Prokineticin Receptor 2 Rare Sequence Variants: Molecular Genetics, Clinical Phenotypes and Therapeutic Outcomes From a Single‐center Cohort

BACKGROUND: Limited data are available regarding the fertility-inducing treatment outcomes and spermatogenic duration in congenital hypogonadotropic hypogonadism patients carrying prokineticin receptor 2 rare sequence variants. OBJECTIVES: We aimed to delineate the rare sequence variant profiles of PROKR2 in a large Chinese cohort with congenital hypogonadotropic hypogonadism, and to characterize the associated clinical phenotypes and therapeutic outcomes. In addition, the reproductive phenotypes and therapeutic outcomes were compared between patients with congenital hypogonadotropic hypogonadism who harbored PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. MATERIALS AND METHODS: Seven unrelated congenital hypogonadotropic hypogonadism probands carrying PROKR2 rare sequence variants (four with Kallmann syndrome and three with normosmic congenital hypogonadotropic hypogonadism) were included. PROKR2 variants in these patients were identified using targeted next-generation sequencing and verified using Sanger sequencing. The pathogenicity of the identified PROKR2 rare sequence variants was assessed according to the American College of Medical Genetics and Genomics guidelines. Baseline clinical characteristics and therapeutic outcomes were retrospectively evaluated and compared between patients with PROKR2 rare sequence variants and those lacking the identified rare sequence variants in established congenital hypogonadotropic hypogonadism-associated genes. RESULTS: We identified a novel PROKR2 rare sequence variant (p.Y154*, a nonsense mutation). Four rare sequence variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. Spermatogenesis was achieved in all six male patients with PROKR2 rare sequence variants who received gonadotropin therapy following an average of 1.28 years. No statistically significant differences were observed in the baseline clinical characteristics and spermatogenic outcomes between patients with PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. CONCLUSION: We observed a lack of evidence for a significant difference in reproductive phenotype or spermatogenic outcomes between male patients with congenital hypogonadotropic hypogonadism and PROKR2 rare sequence variants and those without identified rare sequence variants in congenital hypogonadotropic hypogonadism-associated genes, but this finding is critically limited by the small number of PROKR2 rare sequence variant carriers in our treatment cohort. The identification of a novel PROKR2 rare sequence variant expands the PROKR2 variant spectrum in patients with congenital hypogonadotropic hypogonadism.