Niemann-Pick Disease Type C via the NPC2 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
474 NPC2$540.00 81404 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
This test detects nearly 100 % of NPC2 sequence variants (Patterson, GeneReviews, 2008), which are responsible for ~ 4% of individuals with NPC (Park et al. Hum Mutat 22:313-325, 2003).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 NPC2$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features
Niemann-Pick disease Type C (NPC) is a storage lipid disorder in which defects in the intracellular transport and trafficking of low-density lipoprotein (LDL)-derived cholesterol result in the accumulation if cholesterol and other lipids in tissues. NPC is characterized by an extensive clinical heterogeneity with regards to the age of onset, initial symptoms, severity, and progression. NPC can present at any time from intrauterine to the sixth decade with liver failure, incidental organomegaly, or a wide variety of neurological and psychiatric symptoms. Most common clinical features include enlarged spleen and liver, jaundice, dystonia, seizures, tremor, ataxia, vertical supranuclear gaze palsy, learning difficulty and slurred speech (Patterson, Neurologist 9:301-310, 2003; Vanier and Millat Clin Genet 64:269-281, 2003). Cases with fetal onset, detected ultrasonically in the form of severe ascites, were reported (Maconochie et al. Arch Dis Child 64:1391-1393, 1989; Manning et al. Arch Dis Child 65:335-336, 1990; Spiegel et al. Am J Med Genet 149A:446-450, 2009). NPC occurs worldwide; it is however more common in two genetic isolates. The first isolate is French originating from Normandy and settling in Nova Scotia (Millat et al. Am J Hum Genet 65:1321-1329, 1999); the second is Hispanic originating from the Upper Rio Grande Valley in the US and settling in New Mexico and Colorado (Wenger et al. Am J Dis Child 131:955-961, 1977).
NPC is inherited with an autosomal recessive manner and is further divided into two subtypes, NPC1 and NPC2, based on the causative gene. Clinically, NPC1 and NPC2 are identical. NPC2 (OMIM 607625) is caused by mutations in the NPC2 gene (Naureckiene et al. Science 290:2298-2301, 2000). To date, ~18 different mutations have been reported in patients with variable ethnic background. Mutations included missense, nonsense, frameshift, small insertions and splicing.  The NPC2 gene encodes a soluble lysosomal protein with cholesterol binding properties; it is required for the egress of lipids from the lysosomes
Testing Strategy
This test involves bidirectional DNA sequencing of all 5 exons and splice sites of the NPC2 gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Patients with clinical features suggestive of NPC and with no mutations in the NPC1 gene. Candidates for this test may include: (1) Patients with unexplained dementia or psychiatric illness and cognitive impairment, particularly when accompanied by ataxia, dystonia, or vertical supranuclear gaze palsy, (2) infants with unexplained cholestatic jaundice, and (3) older children with progressive liver disease (Patterson, Neurologist 9:301-310, 2003).


Official Gene Symbol OMIM ID
NPC2 601015
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Niemann-Pick Disease Type C2 607625


Genetic Counselors
  • Maconochie, I. K., (1989). "Fetal ascites: an unusual presentation of Niemann-Pick disease type C." Arch Dis Child 64(10 Spec No): 1391-3. PubMed ID: 2589877
  • Manning, D. J., (1990). "Fetal ascites: an unusual presentation of Niemann-Pick disease type C." Arch Dis Child 65(3): 335-6. PubMed ID: 2334227
  • Marc Patterson (2008). "Niemann-Pick Disease Type C." PubMed ID: 20301473
  • Millat, G., (1999). "Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype." Am J Hum Genet 65(5): 1321-9. PubMed ID: 10521297
  • Naureckiene, S., (2000). "Identification of HE1 as the second gene of Niemann-Pick C disease." Science 290(5500): 2298-301. PubMed ID: 11125141
  • Park, W. D., (2003). "Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1." Hum Mutat 22(4): 313-25. PubMed ID: 12955717
  • Patterson, M. C. (2003). "A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C." Neurologist 9(6): 301-10. PubMed ID: 14629784
  • Spiegel, R., (2009). "The clinical spectrum of fetal Niemann-Pick type C." Am J Med Genet A 149A(3): 446-50. PubMed ID: 19206179
  • Vanier, M. T., Millat, G. (2003). "Niemann-Pick disease type C." Clin Genet 64(4): 269-81. PubMed ID: 12974729
  • Wenger, D. A., (1977). "Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American Children. Juvenile variant of Niemann-Pick Disease with foamy and sea-blue histiocytes." Am J Dis Child 131(9): 955-61. PubMed ID: 900082
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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