Hypogonadotropic Hypogonadism/Kallmann Syndrome via the PROKR2 Gene

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of reproductive disorders due to gonadotropin-releasing hormone (GnRH) deficiency (Buck et al. 2013). IHH is characterized by absent or incomplete pubertal development, low levels of circulating gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), and no other abnormalities of the hypothalamic-pituitary axis. IHH can be divided into two major phenotypes: normosmic hypogonadotropic hypogonadism (nHH), in which hypothalamic GnRH gene regulation or GnRH synthesis, secretion, or signaling is impaired; and Kallmann syndrome (KS), in which the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus is disrupted (Layman 2013). Kallmann syndrome is characterized by an impaired sense of smell (hyposmia or anosmia) alongside delayed or absent puberty. Due to hypothalamic GnRH deficiency, infant boys with KS often demonstrate micropenis and cryptorchidism. Adult males with KS present failure to undergo normal puberty and absence of secondary sexual characteristics. Females with KS usually present with primary amenorrhea or infertility. The degree of both the hypogonadism and the smell deficiency vary significantly even within affected family members (Buck et al. 2013).

To date, ten different genes have been identified to cause KS and nHH (Layman 2013). PROKR2, which encodes G protein-coupled prokineticin receptor-2, is one of these genes. This receptor interacts with prokineticin 2 (produced from the PROK2 gene) and triggers a series of chemical signals. The PROK2/PROKR2 signaling system regulates diverse biological activities, including olfactory bulb (OB) morphogenesis and reproduction, by the activation of downstream signaling pathways (Lin et al. 2002). Autosomal recessive transmission of PROKR2-related disease has been found in some patients, but most patients carrying pathogenic variants in PROKR2 are heterozygotes (Dode et al. 2006; Pitteloud et al. 2007; Cole et al. 2008). At least 48 pathogenic variants in the PROKR2 gene have been identified in individuals with KS and nHH. Notably, most of these variants are missense (Human Gene Mutation Database). These pathogenic variants affect the ability to interact with the ligand and impair G protein-coupling of the receptor. Studies have shown that a loss of PROK2/PROKR2 signaling disrupts the migration and survival of olfactory neurons and GnRH-producing neurons, resulting in defective olfactory bulb morphogenesis, arrested GnRH neuron migration, and consequent hypogonadotropic hypogonadism (Cole et al. 2008; Monnier et al. 2009).

This test is predicted to detect pathogenic variants in 5-7 % of all patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism (Cole et al. 2008; Dode et al. 2013).

To date, no gross deletions or duplication have been reported involving PROKR2.

This test provides full coverage of all coding exons of the PROKR2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).