Episodic Ataxia Type 1 or Hypomagnesemia via the KCNA1 Gene

Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy characterized by short attacks of cerebellar ataxia and dysarthria, and persistent myokymia (Browne et al. 1994; Graves et al. 2014). The first episode of ataxia typically occurs before age 20.

The other KCNA1-associated disease is primary hypomagnesemia, a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting with resulting tetany, cardiac arrhythmias, and seizures (Glaudemans et al. 2009).

Episodic ataxia type 1 (EA1) is an autosomal dominant disorder caused by defects in the KCNA1 gene (Browne et al. 1994). The KCNA1 gene (one coding exon) encodes the voltage-gated K+ channel Kv1.1, which is abundantly expressed in certain neurons as well as on the apical membrane of cells in the distal convoluted tubule (DCT). Documented genetic defects in KCNA1 associated with episodic ataxia type 1 (EA1) include missense (majority), nonsense, small indels and gross deletion (Human Gene Mutation Database).

To date, only one missense variant (identified with linkage in a large pedigree) in KCNA1 has been associated with isolated autosomal dominant hypomagnesemia (Glaudemans et al. 2009).

In a study of 39 unrelated patients with episodic ataxia type 1 (EA1), 10 different pathogenic point variants in KCNA1 were found to account for the genetic basis of 85% of the cohort (Graves et al. 2014).

To date, only one missense variant (identified with linkage in a large pedigree) in KCNA1 has been associated with isolated autosomal dominant hypomagnesemia (Glaudemans et al. 2009).

Only one large deletion involving KCNA1 has been reported (Human Gene Mutation Database). The majority of reported pathogenic variants in KCNA1 are missense variants.

This test provides full coverage of the single coding exon of the KCNA1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.