CLN8 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) in 1999 (Ranta et al., PMID: 10508524). At least 50 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 unrelated probands in 5 publications (PMID: 10508524, 15024724, 19201763, 19807737, 26075876). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function. Of note, the founder variant c.70C>G p.R24G in CLN8 has been implicated in the Northern epilepsy variant of NCL, a slightly more mild and protracted presentation of NCL. Since these patients have intraneuronal brain pathology similar to other patients with classic NCLs (PMID: 10764041), we have “lumped” the conditions for curation. This gene-disease association is supported by a spontaneous non-human animal (dog) model with vision loss, ataxia, and spontaneous seizures (PMID: 24953404). In summary, CLN8 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 classification was approved by the ClinGen Epilepsy Working Group on 9/1/20 (SOP Version 7).
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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