The KCNMA1 gene is associated with an autosomal recessive clinical disorder characterized by a movement disorder, seizures, cerebellar atrophy, and developmental delay in the literature (OMIM 617643). Recent reviews evaluating the phenotype of previously reported patients indicate that homozygous or compound heterozygous variants in KCNMA1 are associated with disorder causing a spectrum of clinical phenotypes consistent with generalized epilepsy-paroxysmal dyskinesia syndrome (PMID 34224328, 31427379). Of note, this gene has also been implicated in autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome, which has been assessed separately.
KCNMA1 was first reported in relation to an autosomal recessive generalized epilepsy-paroxysmal dyskinesia syndrome in 2016 (PMID 27567911). The mechanism for disease is homozygous or compound heterozygous loss-of-function variants.
At least 4 unique variants, including nonsense, frameshift, and missense substitutions, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least three unrelated probands in three publications (PMIDs: 31152168, 27567911, 29545233). Variants in this gene segregated with disease in two siblings from a single family (PMID: 27567911). Parents who were heterozygous for truncating variants were reported to be unaffected (PMIDs: 31152168, 27567911, 29545233). Although the autosomal dominant and autosomal recessive KCNMA1 disorders share overlapping clinical features, the mechanism of disease may be different since haploinsufficiency did not result in clinical features of autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome in relatives who were heterozygous for truncating variants (PMID: 31152168). The autosomal recessive KCNMA1 gene-disease association is supported by an animal model (PMID: 35095492 29545233).
In summary, there is moderate evidence to support this gene disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel Working Group on March 1, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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