Expanding the phenotypic spectrum of PROK2/PROKR2: a recall-by-genotype study.

Rare variants in prokineticin 2 pathway genes (PROK2; PROKR2), cause isolated hypogonadotropic hypogonadism (IHH) in humans, leading to pubertal failure and infertility. In addition to reproduction, this pathway is also implicated in cardiovascular, metabolic, and inflammatory regulation. The role of naturally occurring PROK2/R2 variants in the general population remains unknown. Thus, we aimed to investigate the role of PROK2/R2 variants in the overall human health. We performed a recall-by-genotype study in rare PROK2/R2 variant carriers and non-carrier controls from a large hospital dataset [Massachusetts General Brigham Biobank (MGBB)]. All recalled participants underwent medical history, physical exam, completed detailed questionnaires and laboratory evaluation including a frequently sampled intravenous glucose tolerance test. Continuous and categorical variables were analyzed with a t-test/non-parametric Wilcoxon rank sum test and a Fisher's exact test, respectively. Twenty-five rare PROKR2 variant carriers (11 males and 14 females, mean age 45.6 years ± SD 11.7) and 24 non-carrier controls (16 males and 8 females, mean age 44.8 years ± SD 10) were recruited. Male variant carriers were more likely to seek fertility evaluation compared to non-carrier controls (p = 0.03) and carriers of the founder PROKR2 (p.L173R) variant (44% of the cohort) in both sexes were more likely to be diagnosed with lower gastrointestinal phenotypes compared to controls (p = 0.02). This novel clinical association is in line with the reported role of prokineticin 2 in intestinal smooth muscle function in preclinical models. Rare heterozygous PROK2/R2 variants contribute to known reproductive and novel gastrointestinal phenotypes within a hospital-based population cohort.