CLN6 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) as early as 2002 (Gao et al., Wheeler et al., PMIDs: 11791207, 11727201). Clinical features of NCL include seizures, developmental delay, behavioral changes, vision loss, dementia, and movement and language difficulties. While NCL may be caused by at least a dozen genes in the CLN family (PMID: 26026925), age of onset of CLN6-related NCL varies from late infantile to teenage or adult years, with loss of function variants occurring more frequently in probands with earlier disease onset (PMID: 30561534). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern, and several variants were shared between the late infantile and adult onset conditions. Therefore, the following disease entities have been lumped into one disease entity: NCL6 (MIM #601780) and NCL6, Kufs type, adult onset (MIM #204300). More than 100 variants (including missense, in-frame indel, nonsense, frameshift, splice site, and large deletions) have been reported in humans. Eleven variants in 8 probands reported in 5 publications are included in this curation (PMID: 19135028, 11791207, 11727201, 12673792, 30561534). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function (PMID: 11791207). This gene-disease association is also supported by animal models (murine, canine, feline, and ovine), expression studies, and protein interaction with CLN8, a gene which has also been definitively associated with NCL (PMID: 32597833, 22012656, 24223841, 31331814, 21234413, 32518081, 17046213). In summary, CLN6 is definitively associated with autosomal recessive NCL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This curation was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 12/1/20 (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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