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

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.

Figure 1

Mapping of the coding variants onto the known structure of NPC2. Probably damaging mutations are labeled with red circles. The human NPC2 structural model (from positions 20 to 149) was created using Modeller based on the bovine NPC2 structure (PDB:2HKA). Human NPC2 ribbon is colored according to evolutionary conservation using ConSurf server^; . Cholesterol sulfate (from PDB:2HKA) is shown in sticks. Beta strands are labeled (A to G).

Figure 2

Mapping human N-terminal domain (NTD)-NPC1 mutants. Probably and possibly damaging mutations are labeled with red circles. The human NTD-NPC1 (PDB:3GKI) ribbon was colored according to evolutionary conservation using the ConSurf server^; . Cholesterol is shown in sticks. None of the NTD-NPC1 mutants is located at cholesterol interacting residues.