Most KCNN2 mutations lead to a loss of function of the SK2 channel. They can either replace one amino acid by another (missense mutations) or create a stop codon in the protein. Hence, missense mutations are usually located in domains of the channels critical for protein function. Most mutations are de novo in affected individuals (i.e. are not present in his/ her parents) but a few mutations are transmitted from an affected parent to his / her affected children. In this case, the disease associated with the mutation may be milder.
The 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 variant (de novo/inherited), the segregation of the mutation with the disorder in the family (for inherited variants), the location of the variant in functional domains of the protein and conservation of the amino acid altered in orthologous and paralogous genes. A functional test assessing the impact of the variant on channel may 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.
KCNN2