CLN3 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) in 1995 (Lerner et al., PMID:7553855; MONDO:0016295). NCL patients with variants in CLN3 are typically diagnosed in childhood with gradual loss of vision that evolves into total blindness, epileptic seizures, muscular deterioration, and cognitive decline. There have been individuals reported with biallelic variants in CLN3 and an isolated retinal phenotype; these individuals reached adulthood without the other characteristic features of NCL (PMID:24154662). It is unclear at this time how these cases relate to the classic NCL cases; this curation is exclusively for the relationship between CLN3 and NCL.
Although many individuals with variants in CLN3 have been reported in the literature, five variants (e.g. large deletion, missense, frameshift, stop gained and frameshift) from five probands in four publications are included in this curation (PMIDs: 31926949, 21499717, 19489875 and 19135632). Of note, the recurrent founder variant (a 1.02kb deletion resulting in the removal of exons 7 and 8 and a premature stop codon at exon 9) is the most frequently observed variant and is seen in approximately 96% of patients (PMID:35599949). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is a definitive relationship between CLN3 and autosomal recessive neuronal ceroid lipofuscinosis. 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 GCEP on the meeting date of April 4, 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.