SIK1 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (AD-DEE) in 2015 (Hansen et al., PMID: 25839329). SIK1 is a member of the AMP kinase (AMPK) subfamily and encodes salt-induced kinase 1, a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The gene plays a role in the central nervous system, neuronal development, and a signal transduction pathway involved in nuclear regulation of gene expression (PMID: 25839329).
Four missense variants and three nonsense variants reported in seven probands across two publications (PMIDs: 25839329, 35267137) have been included in this curation. All nonsense variants were downgraded because of functional evidence from Hansen et al. (PMID:25839329) suggesting that p.Glu347Ter, p.Gln614Ter, and p.Gln663Ter all generate a truncated form of SIK1 that is resistant to degradation. The mechanism of pathogenicity is unclear. In summary, there is limited evidence to support the relationship between SIK1 and autosomal dominant developmental and epileptic encephalopathy (AD-DEE). Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
The gene-disease pair was originally evaluated by the Epilepsy GCEP on 10/2/2018 and reached a classification of limited. In 2021, this record went through administrative changes to update the disease term. Evidence was reevaluated on 5/7/2024 under SOP v.10.1. As a result of this reevaluation, the classification did not change and remains at limited.
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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