PROKR2 was first reported in relation to syndromic hypogonadotropic hypogonadism with/without anosmia in 2006 (Dode et al., PMID 17054399). At least 11 missense variants and one frameshift/truncating variant have been reported in humans. Evidence supporting this gene-disease relationship include case level data and experimental data. Excluding variants found as homozygotes in gnomAD and cases with possible digenic inheritance, variants in this gene have been reported in at least 15 probands in 2 publications (PMIDs: 17054399, 18559922) with all cases demonstrating some combination of anosmia and hypogonadotropic hypogonadism. Although the prevalence is not yet clear, patients with PROKR2 variants who have been subject to neuroimaging demonstrate aplasia of the olfactory apparatus in several instances (PMID: 18559922). Imaging based ascertainment strategies (PMID: 23386640) have also identified PROKR2 variants in patients with clinical and/or imaging findings in the spectrum of septooptic dysplasia (septal deficiency, pituitary hypoplasia, optic nerve hypoplasia, schizencephaly, callosal agenesis). PROKR2 related hypogonadotropic hypogonadism is hypothesized to result from interaction with other gene products as overexpression of variant alleles does not squelch function of co-expressed wild type protein (PMID: 18826963). Experimental data for the disease-gene relationship include animal models, in vitro studies of biochemical function, and cell culture assays using non-patient derived cells. More experimental evidence is available in the literature but not cited here.
In summary, PROKR2 is definitively associated with autosomal dominant hypogonadotropic hypogonadism with or without anosmia though prevalence of congenital structural abnormalities of the brain and interaction with other gene variants is not yet fully understood. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 4/26/2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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