Genetic testing for Niemann-Pick Type C disease

Niemann-Pick Type C (NPC) disease is an autosomal recessive lysosomal storage disorder that is characterized biochemically by sequestration of unesterified cholesterol and glycolipids in endosomal and/or lysosomal vesicles with consequent delay in cholesterol esterification. Clinical manifestations include progressive neurodegeneration, variable hepatosplenomegaly and vertical supranuclear gaze palsy. Death often occurs during childhood or early adulthood. NPC is a panethnic disorder with an estimated prevalence of 1 in 150,000. In approximately 95% of families the disease is linked to the NPC-1 gene at 18q11. This gene, isolated in 1997, contains 25 exons encoded by 3.9kb cDNA. Using multiplex PCR and CSGE to screen for mutations in NPC-1, we have tested genomic DNA from 53 unrelated affected individuals. Putative mutations were identified on 64 of 108 (59%) disease alleles and included 38 different DNA alterations located throughout the gene. Types of mutations included: missense (27), nonsense (1), frameshift (5), in-frame deletion (2) and splice site mutation (3). Recurrent mutations were 11061T (allele frequency 19/108, 18%), P237S (allele frequency 4/108, 3.7%), and dell271 (allele frequency 2/108, 1.9%). In addition to the putative mutations, 6 polymorphisms were identified. The finding of a high degree of mutation heterogeneity with many missense alterations creates difficulties for the clinical application of mutation testing in NPC. Although we can determine if missense alterations are in proposed functional domains or at sites conserved across species, we cannot be certain of the pathogenicity of such alterations. DNA alterations identified in affected patients can be used as linkage markers to determine carrier status of at risk relatives. However, the diagnosis in the affected individual must be confirmed by biochemical testing, and must include complementation analysis to establish that the defect is in NPC-1. Mutation analysis for individuals from the general population (e.g. partners of NPC carriers) is likely to result in significant dilemmas in interpretation of results. Funded by a grant from the Ara Parseghian Medical Research Foundation.