SLC12A5 was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2015 (Stödberg et al., PMID:26333769). Typical phenotypes of these probands include infantile-onset focal seizures, which are often epilepsy of infancy with migrating focal seizures, global developmental delay, hypotonia, progressive microcephaly, delayed myelination and cerebral atrophy (PMIDs: 26333769, 27436767, and 31618474). Of note, there has been an assertion made for autosomal dominant susceptibility to idiopathic generalized epilepsy (OMIM:616685). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. The Epilepsy GCEP does not curate for disease susceptibility, so the information about epilepsy susceptibility will not be curated at this time. This entry will only cover autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062).
Ten variants (missense, small in-frame deletions, and splicing) that have been reported in six probands in three publications (PMIDs: 26333769, 27436767, 31618474) are included in this curation. There is some preliminary evidence to suggest that the mechanism of pathogenicity may be loss of function. Electrophysiological studies showed reduced transporter activity of proteins with some variants, although few studies are available at this time (PMIDs: 26333769, 27436767). This gene-disease relationship is also supported by a knockout mouse model in which gentle handling or movement of the mother and littermates triggered seizures (PMID: 12000122). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on March 7, 2023 (SOP Version 9).
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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