Kallmann Syndrome (KS) Panel

Kallmann syndrome (KS) is a genetic disorder that is 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).

KS is caused by pathogenic variants in a number of different genes and to date, ~50% of KS patients are found to have a pathogenic variant that is identifiable. The most common causes of KS are pathogenic variants in the ANOS1 (KAL1), FGFR1, CHD7, PROKR2, PROK2, FGF8, IL17RD, SOX10, GNRHR and TACR3 genes (Balasubramanian et al., 2017. PubMed ID: 20301509). These genes are known to be involved in the formation and migration of GnRH and olfactory neurons. Pathogenic variant in these genes haven been reported to disrupt the migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus. KS can be inherited in an X-linked (ANOS1), autosomal dominant (FGFR1, CHD7, FGF8, IL17RD, SOX10, PROKR2, PROK2), or autosomal recessive manner (PROKR2, PROK2, GNRHR, TACR3). Some of these genes have also been associated with oligogenic inheritance. See individual gene test descriptions for information on molecular biology of gene products.

This multi-gene panel analyzes 10 most common genes associated with Kallmann syndrome (KS). Clinical sensitivity for this NGS test is ~50% (Balasubramanian et al., 2017. PubMed ID: 20301509).

Gross deletions in ANOS1 (KAL1) have been reported in 5-10% of patients with X-linked recessive inheritance (Ahmadzadeh et al., 2015. PubMed ID: 26629483). Only 4 large deletions and genomic complex rearrangements involving FGFR1 were reported in patients affected with Kallmann syndrome or related disorders (Fukami et al., 2013. PubMed ID: 23657145). Gross deletions or duplications of other genes in this panel have not been reported in patients with KS (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).