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  • Test code: 06176
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Niemann-Pick Disease Type C Panel

Test description

The Invitae Niemann-Pick Disease Type C Panel analyzes NPC1 and NPC2, two genes that are known to cause Niemann-Pick disease, type C (NPC), which is a lipid storage disorder. Biallelic variants in either of the two genes result in the same clinical disease. This panel is indicated for any individual in whom NPC is suspected based on clinical, radiologic, or laboratory findings.

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Primary panel (2 genes)
Add-on Lysosomal Acid Lipase Deficiency Gene (1 gene)

In addition to the primary test, clinicians can also choose to include LIPA, which causes lysosomal acid lipase deficiency. Deficiency of the LIPA enzyme can cause increased filipin staining, a finding commonly seen in Niemann-Pick type C. This gene can be added at no additional charge.

LIPA

Add-on Chitotriosidase Deficiency Gene (1 gene)

Chitotriosidase (chito) is an enzyme that can be elevated in some untreated lysosomal storage disorders such as Gaucher disease and Niemann-Pick types A, B, and C. The degree of elevation generally correlates with disease severity. Plasma chito levels are often utilized as a biomarker in the diagnosis and management of individuals with the aforementioned conditions. However, certain variants in the CHIT1 gene lead to absent or decreased chito levels (chito deficiency), limiting the utility of chito as an accurate biomarker unless genotype is available to aid in the interpretation of results. On its own, chito deficiency does not cause any human disease. Therefore, CHIT1 variants known to cause chito deficiency will only be reported if an individual is found to have a confirmed (two causative variants) or a suspected (two Variants of Uncertain Significance, one causative variant, or one causative variant plus one Variant of Uncertain Significance in an affected individual) genetic diagnosis of Niemann-Pick types C. This gene can be added at no additional charge.

CHIT1

  • Niemann-Pick, type C (NPC)

Niemann-Pick, type C (NPC) is a lysosomal storage disease that primarily causes progressive neurovisceral degeneration. In contrast to the majority of lysosomal storage diseases, NPC is due not to an enzymatic defect, but rather to a disorder of intracellular lipid trafficking. NPC is distinct from Niemann-Pick, types A and B, which are due to defects in lysosomal acid sphingomyelinase.

NPC is extremely clinically heterogeneous, with variable ages of presentation (including among siblings), but 90% of patients will present with progressive neurodegeneration. There are five broadly accepted presentations of NPC: pre/perinatal (onset before three months of age), early infantile (onset between three months and two years of age), late-infantile (onset between two and six years of age), juvenile (onset between six and fifteen years of age) and adolescent/adult (onset after 15 years of age). The classic presentation occurs in middle to late childhood. Any or all of the clinical symptoms described below can be observed in patients with NPC.

Neurologic manifestations are often insidious and may initially present with subtle findings such as central hypotonia. Delayed speech and cerebellar signs (e.g., impaired gait, dysphagia) are common. Adult-onset cases often present with cerebellar ataxia. Supranuclear gaze palsy is a hallmark of the disease and has been observed in up to 80% of affected patients. Adults often present with psychiatric illness, such as schizophrenia-like psychosis, depression, and bipolar disorder. Juvenile-onset cases may have behavior problems. Progressive neurologic deterioration occurs in all cases, although adult-onset cases have slower progression. Visceral findings such as hepatosplenomegaly can also be present and are often observed prior to neurologic findings. Additionally, in patients with early-onset disease, or severe NPC2 mutations, pulmonary infiltration with foam cells also occurs.

Premature death occurs in all patients with NPC, most of whom have a life expectancy of 10–25 years. Those with early-onset neurologic symptoms tend to progress faster and have a shorter lifespan. Death is most commonly due to aspiration pneumonia.

Treatment for NPC is primarily symptomatic, but use of the substrate inhibitor miglustat has been approved in Europe and other countries.

Of individuals with a clinical diagnosis of NPC, 95% will have two pathogenic variants in NPC1 and approximately 4% will have biallelic pathogenic variants in NPC2. Less than 1% of cases with clinical and biochemical findings will have pathogenic variants in neither NPC1 or NPC2.

Niemann-Pick type C is inherited in an autosomal recessive pattern.

Prevalence of NPC has been estimated at 1 in 120,000–150,000 in Western European populations, but it is panethnic. Incidence rates are likely underestimated due to the non-specific clinical presentation and the prolonged survival in individuals with later-onset NPC.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CHIT1 NM_003465.2
LIPA NM_000235.3
NPC1 NM_000271.4
NPC2 NM_006432.3