Submission Details

PROK2 was first reported in relation to autosomal dominant Hypogonadotropic hypogonadism 4 with or without anosmia in 2006 (Dodé et al., PMID: 17054399). Hypogonadotropic hypogonadism is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. This can be caused by an isolated defect in gonadotropin-releasing hormone release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, diabetes, sleep disorder, and sensorineural hearing loss, occur with variable frequency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanisms, inheritance patterns, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, hypogonadotropic hypogonadism 4 with or without anosmia (OMIM:610628), Kallman syndrome (KS), and normosic congenital (idiopathic) hypogonadotropic hypogonadism (nIHH) in a semidominant inheritance pattern. Eighteen variants (missense, nonsense, frameshift, duplication, and insertion) that have been reported in 23 probands in 14 publications (PMIDs: 17054399, 17959774, 18559922, 18682503, 18985070, 23082007, 23596439, 24002956, 24031091, 25077900, 26141714, 30098700, 32870266, 33140874) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (animal models, expression studies, biochemical function, and protein interaction) (PMIDs: 12427552, 12604792, 15976302, 17093083, 17959774, 19784373, 24633064). One mouse model phenocopies hypogonadotropic hypogonadism and the expression study demonstrates PROK2 involvement in olfactory bulb neurogenesis. Another mouse model demonstrates that LOF in PROK2 can cause attenuated estrous cycles along with other circadian rhythms including sleep cycles and blood glucose regulation. PROK2 is expressed in the olfactory bulb and testis, proposed to modulate GnRH release as an SCN output molecule regulating circadian rhythms, and interacts with PROKR2 which is definitively associated with hypogonadotropic hypogonadism. In summary, PROK2 is definitively associated with semidominant Hypogonadotropic hypogonadism 4 with or without anosmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This has been approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 03/22/2022 (SOP Version 8).