NPC1

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0016307

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0016310

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0016309

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0016308

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009757

Submitter: ClinGen

The relationship between NPC1 and Niemann-Pick disease type C1, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of February 28, 2022. NPC is characterized by abnormal intracellular accumulation of cholesterol (which can be detected by filipin staining and, more recently by measurement of oxysterols) and glycosphingolipids in various tissues. It typically presents in childhood with hepatosplenomegaly and progressive neurodegeneration characterized by cerebellar ataxia, dysphagia, and dementia, resulting in a shortened lifespan. There are more severe infantile forms, the most severe of which is the neonatal, rapidly progressing cholestatic form. Late-onset forms also occur, presenting with early-onset dementia or psychiatric symptoms (Erikson et al, 2013, PMID: 23292954; Newton et al, PMID 30205941; Patterson, 2020, PMID: 20301473). There is no curative treatment. Miglustat has been approved for the management of neurologic symptoms in some countries (Patterson, 2020, PMID: 20301473). Features of NPC that can be prenatally identified by fetal imaging include ascites in the third trimester, splenomegaly, hepatomegaly, placentomegaly, and hydrops. Neonates may have hypotonia, thrombocytopenia, and jaundice. Death in the neonatal period from respiratory or liver failure is common with these early presenting cases (PMIDs: 18554276, 19206179, 23597521, 26563327, 28951965, 28802248). About 95% of cases of NPC are caused by biallelic variants in NPC1 and 5% by variants in NPC2 (Patterson, 2020, PMID: 20301473). NPC1 encodes a an integral membrane protein with at least 13 transmembrane domains and a putative sterol sensing domain, located in the lysosomal membrane and involved in transport of cholesterol from the lysosome to the cytoplasm (Bauer et al, 2002, PMID 11754101). Biallelic variants in NPC1 were first reported in patients with NPC in 1997 (Carstea et al, PMID: 9211849). Since then, over 200 disease-associated variants have been reported (Patterson, 2020, PMID: 20301473). In this curation, data on 10 unique variants (5 missense – one of which also impacts splicing, 3 nonsense, and 2 frameshift) from 10 probands from 4 publications were collected (Greer et al, 1998, PMID: 9634529; Yamomoto et al, 1999, PMID: 10480349; Millat et al 2001, PMID: 11333381; Fancello et al, 2009, PMID: 19252935). This includes c.3182T>C (p.Ile1061Thr), which is reported to account for 15%-20% of pathogenic variants in Western Europe the USA (PMID: 16126423). In addition, data on c.2974G>T (p.Gly992Trp), a founder variant in the Acadian population of Nova Scotia (Greer et al, 1998, PMID: 9634529) was also curated. This variant was reported to cause a condition originally described as Niemann-Pick disease, type D (NPD), but which now known to be a subtype of NPC. Segregation data was also available from the Nova Scotian population (Greer et al, 1999, PMID: 10361985). The disease mechanism is loss of function. 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 NPC1, which is consistent with the biochemical and clinical findings in patients (Ifante et al, 2008, PMID: 18772377; Li et al, 2016, PMID: 27551080; Newton et al, 2018, PMID: 30205942), interaction of NPC1 with NPC2, which is encoded by another gene involved in Niemann-Pick C disease (Deffieu and Pfeffer, 2011, PMID: 22065762), the biochemical and clinical features of a mouse with a knock-in human variant (Praggastis et al, 2015, PMID: 26019327), rescue of abnormal cholesterol accumulation in NPC fibroblasts by expression of NPC1 cDNA (Carstea et al, 1997; PMID: 9211849) and the impact of gene therapy in a mouse knock out model (Kurokawa et al, 2021, PMID: 33256498). Additional experimental evidence is available in the literature but the maximum points for experimental evidence (6 points) has been reached. In summary, NPC1 is definitively associated with Niemann-Pick disease type C1. 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 the the Lysosomal Diseases GCEP on March 1, 2022 (SOP V8), and details of the prenatal presentation of the disease, provided by the ClinGen Prenatal GCEP were added on Jan 9, 2025.

Inheritance Pattern: AR

Disease ID:MONDO:0016306

Submitter: Orphanet