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PURPOSE: Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important. METHOD: We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency. RESULTS: Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,000-1/36,000. CONCLUSION: We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.

Original publication




Journal article


Genet Med

Publication Date





41 - 48


Adolescent, Adult, Carrier Proteins, Exome, Female, Gene Frequency, Genetic Association Studies, Genetic Testing, Genetic Variation, Glycoproteins, High-Throughput Nucleotide Sequencing, Humans, Incidence, Male, Membrane Glycoproteins, Models, Molecular, Mutation, Niemann-Pick Disease, Type B, Niemann-Pick Disease, Type C, Oxidoreductases Acting on CH-CH Group Donors, Predictive Value of Tests, Protein Structure, Secondary