Test Catalog

Test ID: NPCZ    
Niemann-Pick Type C Disease, Full Gene Analysis, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Second-tier test for confirming a biochemical diagnosis of Niemann-Pick type C (NPC)


Carrier testing of individuals with a family history of NPC in cases when an affected individual is not available for testing or disease-causing variants have not been identified

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Testing includes full gene sequencing of the NPC1 and NPC2 genes, including analysis for large deletions and duplications.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

If a skin biopsy is received, fibroblast culture will be performed at an additional charge.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Niemann-Pick type C (NPC) is an inherited disorder of cholesterol transport that results in an accumulation of unesterified cholesterol and lipids in the lysosomal/endosomal system and in various tissues. Although NPC belongs to a group of lysosomal disorders including Niemann-Pick types A and B, these diseases are metabolically and genetically distinct. Niemann-Pick types A and B are caused by variant in the SMPD1 gene, which encodes the enzyme sphingomyelinase, whereas NPC is caused by variants in the NPC1 or NPC2 genes.


The incidence of NPC is approximately 1 in 120,000 to 1 in 150,000 live births. Age of onset is variable and ranges from the perinatal period to adulthood. Clinical presentation is also highly variable. Infants may present with or without liver disease (hepatosplenomegaly) and respiratory failure. Those without liver and pulmonary disease may present with hypotonia and developmental delay. Most individuals are diagnosed during childhood with symptoms including ataxia, vertical supranuclear gaze palsy, dystonia, progressive speech deterioration, and seizures resulting in death by the second or third decade of life. Adult-onset NPC is associated with a slower progression and is characterized by neurologic and psychiatric problems.


NPC is inherited in an autosomal recessive manner, in which affected individuals carry 2 variants in either the NPC1 or NPC2 gene. Most variants are family specific, although there are 2 variants in the NPC1 gene that are more common than others. The G992W alteration is common in the French Acadian population of Nova Scotia. The I1061T alteration is the most common variant worldwide, and is seen in patients of Hispanic and Western European (United Kingdom and France) descent. Full gene sequencing and analysis for large deletions and duplications of the NPC1 and NPC2 genes detect less common disease-causing variants. 


The recommended first-tier test to screen for NPC is a biochemical test measuring oxysterols (OXNP / Oxysterols, Plasma). Molecular testing provides confirmation of a biochemical diagnosis or a basis for carrier testing of family members. Individuals with abnormal biochemical results are more likely to have 2 identifiable variants by molecular testing. Additionally, cholesterol esterification coupled with filipin staining on a fibroblast specimen (NIEM / Niemann-Pick Type C Detection, Fibroblasts) can aid in diagnosis.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of, Niemann-Pick type C (NPC) disease may have a variant that is not identified by this method (eg, promoter alterations, deep intronic alterations). The absence of a variant, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of NPC. For carrier testing, it is important to first document the presence of NPC1 or NPC2 gene variants in an affected family member.


In some cases, DNA alterations of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.


In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. NP-C Guidelines Working Group, Wraith JE, Baumgartner MR, et al: Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009 Sep-Oct;98(1-2):152-65

3. Park WD, O'Brien JF, Lundquist PA, et al: 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. 2003 Oct;22(4):313-325

4. Vanier MT: Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5:16

Special Instructions Library of PDFs including pertinent information and forms related to the test