Kallmann Syndrome via the KAL1(ANOS1) Gene

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of reproductive disorders due to gonadotropin-releasing hormone (GnRH) deficiency (Layman 2013). IHH is characterized by absent or incomplete pubertal development, low levels of circulating gonadotropins and testosterone, 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 this migratory pathway of GnRH and olfactory neurons from the nasal region into the hypothalamus is disrupted.

Kallmann syndrome is characterized by an impaired sense of smell (hyposmia or anosmia) alongside delayed or absent puberty. It is also characterized by a variety of nonreproductive anomalies including involuntary upper limb mirror movements (bimanual synkinesis), abnormal eye movements, congenital ptosis, abnormal visual spatial attention, hearing impairment, agenesis of the corpus callosum, unilateral (occasionally bilateral) renal agenesis, cleft lip or palate, agenesis of one or several teeth (hypodontia), obesity and other less observed anomalies. The degree of both the hypogonadism and the smell deficiency vary significantly even within affected family members.

Kallmann syndrome 1 is an X-linked recessive disorder caused by defects in the KAL1(ANOS1) gene. Since it is X-linked recessive and the ANOS1 gene escapes X-inactivation, there is not convincing evidence that ANOS1 mutations cause KS in females (Layman 2013).

Kallmann syndrome 1 is an X-linked recessive disorder caused by defects in the ANOS1 gene. The ANOS1 gene has 14 coding exons that encode the extracellular glycoprotein anosmin-1 (ANOS1). Genetic defects of ANOS1 include missense, nonsense, splicing site mutations and small indels. Large deletions and duplication are commonly found within the ANOS1 gene or encompassing multiple genes including ANOS1 (Human Gene Mutation Database).

The prevalence of ANOS1 mutations has been estimated to be 5–10% in males KS patients (both sporadic and familial) and much higher (30-70%) in the clearly X-linked recessive families (Layman 2013). Given that large deletions and duplications are common in the ANOS1 region, ANOS1 mutation detection rate through sequencing is expected to be lower than this number.

This test provides full coverage of all coding exons of the ANOS1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.