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Genet Med. 2016 Jan;18(1):41-8. doi: 10.1038/gim.2015.25. Epub 2015 Mar 12.

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.

Author information

1
Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
2
Department of Pharmacology, University of Oxford, Oxford, UK.
3
Department of Physiology, Anatomy and Genetics, MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
4
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, Missouri, USA.
5
Statistical Genetics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
6
Clinical Genomics Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.

Abstract

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.

PMID:
25764212
PMCID:
PMC4486368
DOI:
10.1038/gim.2015.25
[Indexed for MEDLINE]
Free PMC Article

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