Submission Details

The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of progressive neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent storage material. Biallelic pathogenic variants in CTSF cause neuronal ceroid lipofuscinosis, type 13 (NCL13) or Kufs disease type B, an adult-onset form of NCL without reported retinal disease. Kufs disease type B is characterized by progressive cognitive decline, tremor, ataxia, myoclonus, rigidity, perioral dyskinesias, dysarthria, seizures, hyperreflexia, and behavior changes. Affected individuals may be diagnosed with frontotemporal dementia. Onset of symptoms in reported individuals ranges from the third to sixth decade and affected individuals demonstrate cerebral and cerebellar atrophy on MRI and the characteristic autofluorescent storage bodies in a variety of cell types. CTSF encodes for cathepsin F, a lysosomal cysteine protease, and the disease mechanism is loss of function. Fifteen different disease-causing variants have been reported in families in the literature, in the homozygous or compound heterozygous state. The pathogenic variant spectrum includes nonsense, frameshift, canonical splice site, missense variants, and a multi-exonic deletion (Smith et al, PMID 23297359; Di Fabio et al, PMID 25274848; Bras et al, PMID 27524508; van der Zee et al, PMID 27668283; Blauwendraat et al, PMID 28749476; Wang et al, PMID 29120254; Kulkarni et al, PMID 33578366; Wagner et al, PMID 34561610; Gultekin et al, PMID 35139754). A number of the reported families demonstrate complete co-segregation of the CTSF variants with disease, and one family from a small isolated Italian community demonstrates pseudo-dominant inheritance (Smith et al, PMID 23297359; van der Zee et al, PMID 27668283; Di Fabio et al, PMID 25274848). Supporting experimental evidence includes a non-human model organism; a Ctsf deficient mouse model that developed neurological disease comparable to the human phenotype and an accumulation of autofluorescent granules in brain tissue (Tang et al, 16508006; Smith et al, PMID 23297359).

Case level genetic evidence provides a score of 12 points and experimental evidence provides a score of 2 points, resulting in a total score of 14 points. Evidence supporting an association between CTSF and NCL has been replicated over time; therefore, the gene-disease validity has been classified as DEFINITIVE. This classification was approved by the ClinGen Epilepsy GCEP on March 1, 2022 (SOP Version 8).