PPT1 was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) (MONDO:0016295) in 1998 (Mitchison et al., PMID: 9425237). Of note, NCL is also referred to as Batten disease and, in the case of NCL caused by variants in PPT1, ceroid lipofuscinosis, neuronal 1 (CLN1). NCL is a lysosomal storage disorder that is often characterized by intracellular accumulation of autofluorescent lipopigments and progressive neurodegeneration beginning in childhood, and can involve a variety of phenotypes including: seizures, cognitive decline, vision deterioration, blindness, and brain atrophy. Nine variants (missense, frameshift, nonsense, and intronic) that have been reported in 12 probands in three publications are included in this curation (PMIDs: 31741823, 19793312, 19302939). Of all variants described, one nonsense variant, p.Arg151*, has been reported to account for 40% of all known alleles (PMID: 9664077). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models (PMIDs: 11717424, 31289301). In summary, there is definitive evidence supporting the relationship between PPT1 and neuronal ceroid lipofuscinosis (MONDO:0016295). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was originally approved by the ClinGen Epilepsy GCEP on the meeting date June 16, 2020 (SOP Version 7). As of March 30, 2023, this record underwent administrative updates. Evidence scoring was modified to reflect the new recommendations made in SOP Version 9. An evidence summary was also added. No new evidence was reviewed or added at that time. Most recently, on June 10, 2024, this record underwent further administrative updates to include the ClinGen Retina GCEP as a secondary contributor. Additional explanatory text was added to the evidence summary, but the original evidence was not changed.
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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