Submission Details

The relationship between NPC2 and Niemann-Pick disease, type C2, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022.

Niemann-Pick disease, type C (NPC) is characterized by abnormal intracellular accumulation of cholesterol (which can be detected by filipin staining or, more recently, by measurement of oxysterols) and glycosphingolipids in various tissues. The clinical presentation typically depends upon age of onset and includes visceral features, such as hepatosplenomegaly, jaundice, and pulmonary infiltrates (in some cases) in infancy, and neurological features including hypotonia and developmental delay in late infancy, with later development of ataxia, dysarthria, dysphagia, seizures, dystonia, gelastic cataplexy, and cognitive impairment. Older teenagers and young adults may present with early-onset dementia or psychiatric manifestations (Patterson, 2020, PMID: 20301473).

About 95% of cases of NPC are caused by biallelic variants in NPC1 and 5% by variants in NPC2; symptoms in individuals with variants in these genes are indistinguishable (Patterson, 2020, PMID: 20301473).

NPC2 encodes a soluble lysosomal protein with cholesterol binding properties (Xu et al, PMID: 31843136). Biallelic variants in NPC2 were first reported in patients with Niemann-Pick disease, type C2, by Naureckiene et al in 2000 (PMID: 11125141). Since then, over 20 variants have been reported in about 50 cases worldwide (Xu et al, 2019, PMID: 31843136). The disease mechanism is loss of function. In this curation, data on 8 unique variants (missense, nonsense, splice site) from 8 probands from 3 publications were collected (Millat et al, 2001, PMID: 11567215; Chikk et al, 2005, PMID: 15937921; Verot et al, 2007, PMID: 17470133). This includes c.58G>T (p.Glu20Ter), which is reported to account for >50% of Niemann Pick type C2 alleles (Millat et al, 2001, PMID: 11567215). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached.

Experimental evidence supporting this gene-disease relationship includes the biochemical function of NPC2, which is consistent with the biochemical and clinical findings in patients (Xu et al, PMID: 31843136); interaction of NPC2 with NPC1, another gene involved in Niemann-Pick disease, type C (Deffieu and Pfeffer, 2011, PMID: 22065762); functional alteration studies demonstrating the importance of glycosylation of Asn58 in the localization and function of NPC2 (Chikh et al, 2004, PMID: 15542393); the biochemical, clinical features, and histological features of an NPC2 hypomorphic mouse (Sleat et al, 2004, PMID: 15071184); rescue of abnormal cholesterol accumulation in NPC2 fibroblasts by medium conditioned by NPC2-expressing cells (Naureckiene et al, 2000, PMID: 11125141); and rescue of phenotypic features and visceral cholesterol accumulation in NPC-/- mice by treatment with bivine NPC protein (Nielsen et al 22073306). Additional experimental evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached.

In summary, NPC2 is definitively associated with Niemann-Pick disease, type C2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the Lysosomal Diseases GCEP on April 5th, 2022 (SOP version #8).