Hypogonadotropic Hypogonadism/Kallmann Syndrome via the FEZF1 Gene

Kallmann syndrome (KS) is a genetic disorder characterized by delayed or absent puberty along with an impaired or absent sense of smell (hyposmia or anosmia). This disorder is a form of idiopathic hypogonadotropic hypogonadism (IHH), which is a group of reproductive conditions due to gonadotropin-releasing hormone (GnRH) deficiency (Dodé and Hardelin. 2009. PubMed ID: 18985070; Layman. 2013. PubMed ID: 23650337). Patients with IHH usually present with absent or incomplete pubertal development, low levels of circulating gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), but 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.

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 lack of the sense of smell is the key feature that distinguishes Kallmann syndrome from other forms of hypogonadotropic hypogonadism. The degree of both the hypogonadism and the smell deficiency vary significantly even within affected family members. In addition to reproductive symptoms, many KS patients exhibit a wide variety of additional signs and symptoms. Commonly recognized non-reproductive features that may be present in KS patients include: digital synkinesia, unilateral renal agenesis, cleft lip and/or palate, dental agenesis, hearing loss, and abnormal eye movements (Kaplan et al. 2010. PubMed ID: 20949504; Layman. 2013. PubMed ID: 23650337; Balasubramanian et al. 2017. PubMed ID: 20301509).

To date, more than ten different genes have been identified to cause KS and nHH (Layman. 2013. PubMed ID: 23650337). FEZF1-related KS is inherited in an autosomal recessive manner. FEZF1, which encode a transcriptional repressor, is one of the genes. FEZF1 is a zinc-finger gene encoding a transcriptional factor. It is highly and selectively present during embryogenesis in the olfactory epithelium, amygdala, and hypothalamus. Fezf1-deficient mice have shown impaired axonal projection of pioneer olfactory receptor neurons (ORNs) (Hirata et al. 2006. PubMed ID: 16971467). Homozygous missense variants and a small deletion in FEZF1 have been found in patients with KS (Kotan et al. 2014. PubMed ID: 25192046).

To date, only two pathogenic variants have been reported in FEZF1 (Kotan et al. 2014. PubMed ID: 25192046). Abnormalities in FEZF1 therefore appear to be a relatively rare cause of disease.

This test provides full coverage of all coding exons of the FEZF1 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).