Submission Details

Neuronal ceroid lipofuscinoses (NCLs) are progressive neurodegenerative diseases characterized by mental and motor deterioration, epilepsy, visual loss, ataxia, and a reduced life span. The unifying finding in NCL patients is the accumulation, in neurons and many other cell types, of autofluorescent storage material. There are 13 subtypes of NCLs that are categorized based on the particular gene that is mutated.

CLN5 is associated with autosomal recessive NCL, with typical onset in preschool or early childhood, often described as variant late infantile NCL (vLINCL). CLN5 is an intracellular trafficking protein that is implicated in recruitment of the retromer complex to endosomes. It is translated into a preprotein with an N-terminal transmembrane domain that is cleaved to form the active soluble protein. The historic nomenclature differs from the current nomenclature used in ClinVar and some more recent publications by 147 nucleotides / 49 amino acids.

CLN5 was first identified as a cause of NCL in 1998 in a study that identified a founder mutation (c.1026_1027AT AKA AKA c.1175_1176delAT) in individuals with vLINCL from 17 familes (Savukoski et al., 1998, PMID: 9662406). Since then, more than 50 variants have been reported, and more than half are protein truncating (Kousi et al., 2012, PMID: 21990111; https://www.ucl.ac.uk/ncl//mutation.shtml). Eight symptomatic probands from unrelated families with homozygous or compound heterozygous CLN5 variants reported by five studies were scored for genetic evidence (PMID: 9662406, 20157158, 19201763, 18684116, 21990111). Four probands had homozygous nonsense or frameshift variants in the last exon that are expected to cause protein truncation and in the absence of functional studies are not proven to be null so were given a modified score. The remaining probands were homozygous or compound heterozygous for two variants in trans that were proven/predicted to be null, and were given scores of 2. Functional studies were used to upgrade the points for two probands with frameshift variants in the last exon. No LOD scores could be calculated from these families because only a single affected individual was reported or detailed family information was not provided. Supporting experimental evidence includes protein interaction with CLN2 (12134079), non-human model organisms (dog: 27203721), and rescue in non-human model organisms by adeno associated virus-mediated gene transfer (mouse: 17637720; dog: 26560358). In summary, a score of 12 was given to genetic evidence, and 2.5 to experimental evidence, reaching 14.5 in total. The association between CLN5 and NCL has been replicated over time and is therefore considered definitive.