The Invitae Niemann-Pick Type C Panel analyzes NPC1 and NPC2, two genes that are known to cause Niemann-Pick type C (NPC). Biallelic variants in either of the two genes result in the same clinical disease. This panel is indicated for any individual in whom Niemann-Pick, type C, is suspected based on clinical, radiologic, or laboratory findings. Neuropathological changes occur prior to onset of clinical symptoms, so early diagnosis is of critical importance.
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 bi-polar 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 progressive neurologic disease and is often related to aspirations.
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 nor 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.
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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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
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|