Molecular characteristics

Most KCNN2 pathogenic variants identified so far are either truncating (nonsense, frameshifts, splice site variants) or missense variants leading to an apparent loss-of-function of the channel. Missense variants are mainly located in transmembrane domains or the domains important for the channel function, such as the pore of the channel.
The precise mechanisms by which KCNN2 mutations lead to disease is not completely elucidated so far, but all KCNN2 mutations studied led to a complete loss-of-function of the mutant channel expressed alone.
Identification of a KCNN2 mutation can be achieved by different methods: targeted analysis of the KCNN2 gene by Sanger sequencing or next-generation sequencing; gene panel sequencing including KCNN2, exome or genome sequencing. Intragenic deletions have to be searched for by appropriate methods like microarrays, multiplex ligation-dependent probe amplification (MLPA) analysis or any method allowing to assess the copy number of each exon.
Interpretation of a novel KCNN2 variant should be performed according to the ACMG criteria, taking into account the inheritance of the mutation (de novo/inherited), the segregation of the mutation with the disorder in the family (for inherited variants ), the location of the mutation on the protein and conservation of the amino acid altered in orthologues and paralogues. A functional test of the variant on the channel properties can also be required to conclude that the variant is pathogenic. Although KCNN2 has a probability of being loss-of-function intolerant (pLI) score of 0.99, truncating variants should be interpreted with caution, as they have been described in a few healthy individuals.