Niemann-Pick Disease Type C Panel

Niemann-Pick disease Type C (NPC) is a lipid storage disorder in which defects in the intracellular transport and trafficking of low-density lipoprotein (LDL)-derived cholesterol result in the accumulation of cholesterol and other lipids in tissues. NPC has a prevalence of 1:90,000 to 100,000 live births although this may be an underestimate due to the clinical heterogeniety of the disorder (Papandreou and Gissen 2016). The disease is characterized by extensive clinical heterogeneity with respect 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 2003; Vanier and Millat 2003; Papandreou and Gissen 2016). Cases with fetal onset, detected ultrasonically in the form of severe ascites, have been reported (Maconochie 1989; Manning et al. 1990; Spiegel et al. 2009). NPC occurs worldwide; it is however more common in two genetic isolates: a French isolate originating from Normandy and settling in Nova Scotia (Millat et al. 1999); and an Hispanic isolate originating from the Upper Rio Grande Valley in the USA and settling in New Mexico and Colorado (Wenger et al. 1977).

NPC is inherited in 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. NPC1 accounts for ~95% of cases and is caused by variants in the NPC1 gene (Carstea et al. 1997; Papandreau and Gissen 2016). The NPC1 gene encodes a lysosomal-endosomal transmembrane protein required for the egress of lipids from the lysosome. Over 400 pathogenic variants, distributed throughout the gene, have been reported and include missense/nonsense (~70%), small insertion/deletions (~22%) and splicing (< 1%). Gross insertions and deletions are apparently rare (Human Gene Mutation Database). Two founder mutations have been identified. The p.Gly992Trp variant was found in all patients from the Nova Scotia isolate (Greer et al. 1998). The p.Ile1061Thr variant, which apparently originated in Western Europe, was detected in all Hispanic patients from the Upper Rio Grande isolate (Millat et al. 1999).

NPC2 accounts for ~4% of cases and is caused by variants in the NPC2 gene (Papandreau and Gissen 2016). The NPC2 gene encodes a soluble lysosomal protein with cholesterol binding properties; it is required for the egress of lipids from the lysosomes. To date, 25 pathogenic variants have been reported in NPC2 including missense/nonsense (~76%), splicing (~12%), and small deletions (~12%). No large deletions or duplications have been reported in NPC2 (Human Gene Mutation Database).

The remaining ~1% of cases of NPC are biochemically-confirmed cases with no identified variants in NPC1 or NPC2.

This test is be expected to detect variants in >95% of individuals with biochemically-confirmed NPC (Papandreou and Gissen 2016).

Although rare, gross deletions and duplications have been reported in the NPC1 gene. None of the variants reported to date in NPC2 have been gross deletions or duplications (Human Gene Mutation Database).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.