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

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Christopher A WassifForbes D Porter

Abstract

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. 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. 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. We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incompl...Continue Reading

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Citations

Mar 5, 2016·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Ya Hui HungAshley I Bush
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Methods Mentioned

BETA
exome sequencing
exome sequencing.
reverse transcription-PCR

Clinical Trials Mentioned

NCT01747135

Software Mentioned

Mutation assessor
TASSER
script
- 2
SIFT
Polyphen
Perl
ClinSeq
SIFT assessor
MaxEntScan

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