Niemann-Pick Disease Type C: NPC1 and NPC2 Gene Sequencing

Condition Description

Niemann-Pick Disease, Type C (NPD-C) is an autosomal recessive lipid storage disorder caused by a defect in esterification of exogenously derived low-density lipoprotein cholesterol. This impairment in the transport of cholesterol and glycosphingolipids leads the accumulation of cholesterol in the lysosomes[1,2]. The accumulation of lipids in lysosomes leads to engorged lysosomes, deficiencies in membrane cholesterol, and eventually cell death. NPD-C can present at any stage in life. Infants may present with severe liver disease, organomegaly, pulmonary disease, hypotonia, and developmental delay. Idiopathic neonatal cholestatis is considered a significant indicator of NPD-C. Typical presentation in older children may present with ataxia, vertical and horizontal supranuclear gaze palsy, dementia, dystonia, enlarged liver and spleen, and seizures. As the disease progresses, patients have difficulty coordinating the muscles for eating, walking, and speaking. In the adult onset form of the disease, affected individuals typically present with dementia and psychiatric symptoms. The biochemical diagnosis is made by evaluating LDL-cholesterol esterification in cultured fibroblasts and filipin staining showing accumulation of unesterified cholesterol. Mutations in the NPC1 and NPC2 genes are responsible for NPD-C. Complementation studies indicate that the vast majority of individuals with NPD-C have mutations in the NPC1 gene[3] with ~4% of cases mutations having mutations in the NPC2 gene[4]. Although there is a common NPC1 mutation found in individuals of Mexican descent in the Rio Grande valley and a common NPC2 mutation found in individuals from Nova Scotia, there are over 200 other mutations have been identified in the NPC1 and NPC2 genes. The majority of NPC1 and NPC2 mutations are private missense mutations [4-6]. For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (NE). For questions about testing for NPD-C disease, call EGL Genetics at (470) 378-2200 or (855) 831-7447. For further clinical information about lysosomal storage diseases, including management and treatment, call the Emory Lysosomal Storage Disease Center at (404) 778-8565 or (800) 200-1524.

1). Neufeld et al. (1999) The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem 274:9627-35
2). Wojtanik KM and Liscum L (2003) The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem 278:14850-6
3). Vanier et al. (1996) Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet 58:118-25.
4). Park et al. (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 22:313-25.
5). Scott C and Ioannou YA (2004) The NPC1 protein: structure implies function. Biochim Biophys Acta 1685:8-13
6). Fernandez-Valero, et al. (2005) Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet 68:245-54

Genes (2)


This test is indicated for:
  • Confirmation of a clinical diagnosis of Niemann-Pick Disease, Type C
  • Prenatal testing for known familial mutations.
  • Carrier testing in adults with a family history of Niemann-Pick Disease, Type C.


Next Generation Sequencing: In-solution hybridization of all coding exons is performed on the patient's genomic DNA. Although some deep intronic regions may also be analyzed, this assay is not meant to interrogate most promoter regions, deep intronic regions, or other regulatory elements, and does not detect single or multi-exon deletions or duplications. Direct sequencing of the captured regions is performed using next generation sequencing. The patient's gene sequences are then compared to a standard reference sequence. Potentially causative variants and areas of low coverage are Sanger-sequenced. Sequence variations are classified as pathogenic, likely pathogenic, benign, likely benign, or variants of unknown significance. Variants of unknown significance may require further studies of the patient and/or family members.


Clinical Sensitivity: In a study of 143 unrelated patients with NPC, Park et al. identified mutations in 251 of the 286 alleles assessed, giving a detection rate of 88% [4]. Detection may be lower in variant forms.

Analytical Sensitivity: ~99%

Prevalence: The estimated prevalence of all lysosomal storage disorders is 2-5 per 100,000. The prevalence of NPD-C is not specifically known, but is likely to be rare and may vary by ethnicity.

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample. Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside EGL Genetics, please submit a copy of the sequencing report with the test requisition. Contact the laboratory if further information is needed.
  • Mucopolysaccharide Screen (Urine GAG) (GA)
  • Known Mutation Analysis (KM) is available to test family members.
  • Deletion/Duplication Assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition or contact the laboratory for more information.
  • Prenatal testing is available for known familial mutations only. Please call the Laboratory Genetic Counselor for specific requirements for prenatal testing before collecting a fetal sample.

How to Order