• Test code: 06201
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Prosaposin Deficiency Test

Test description

The Invitae Prosaposin Deficiency Test analyzes the PSAP gene, which is associated with combined saposin deficiency (PSAPD) and rare cases of metachromatic leukodystrophy and Gaucher disease. Additionally, there is also preliminary evidence supporting a correlation with atypical Krabbe disease due to saposin A deficiency.

Genetic testing of this gene may confirm diagnosis of patients whose clinical symptoms and biochemical findings indicate a prosaposin deficiency. Identification of a disease-causing variant may help guide medical management and help predict disease progression and outcome for the patient, as well as, guide reproductive decisions and identify carrier relatives.

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Primary panel (1 gene)

Alternative tests to consider

For a broader analysis of the genetics of lysosomal storage disorders:

  • combined saposin deficiency

Combined saposin deficiency is a fatal neonatal lysosomal storage disorder characterized by the abnormal accumulation of sphingolipids in the nervous system and other organs, such as liver and spleen. Individuals affected with compound prosaposin deficiency present with severe neurological manifestations including generalized hypotonia, seizures, hyperkinetic behaviour, myoclonus, respiratory insufficiency and hepatosplenomegaly. Individuals affected by PSAPD usually die from respiratory failure due to frequent pulmonary infections.

Proper sphingolipid metabolism is crucial for cell membrane integrity, especially in neurons, and for immune functions in cells. Prosaposin is the precursor of four smaller proteins known as saposins A, B, C and D. These four mature saposins, as well as, the full length prosaposin protein are non-enzymatic glycoproteins that act as essential cofactors for lysosomal hydrolases involved in the sphingolipids metabolism. Disease-causing variants that result in the absence of all five PSAP-derived saposins result in a generalized severe lipid storage disorder affecting several sphingolipids, including ceramide, glucosylceramide, gangliosides, galactosylceramide and sulfatides. Complete loss of saposins and the resulting generalized defects in sphingolipid metabolism are thought to be the cause of combined saposin deficiency.

The clinical sensitivity for this test is unknown at this time. Few individuals with complex prosaposin deficiency have been described to date making it difficult to estimate the clinical sensitivity of this test.

Combined saposin deficiency is inherited in an autosomal recessive pattern.

At this time, the prevalence of combined saposin deficiency is unknown due to the rarity of this disorder.

Considerations for testing include:

  • presence of Gaucher-like cells in the bone-marrow
  • loss of galactocerebrosidase activity in leukocytes and fibroblasts
  • increased levels of glucosylceramide, lactosylceramide and ceramide
  • abnormal typical profile of urinary glycolipids (i.e. massive excretion of globotriaosylceramide, sulfatides and other sphingolipids)

  1. Schnabel, D, et al. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. J. Biol. Chem. 1992; 267(5):3312-5. PMID: 1371116
  2. Spiegel, R, et al. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol. Genet. Metab. 2005; 84(2):160-6. PMID: 15773042
  3. Tylki-Szymańska, A, et al. Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin. Genet. 2007; 72(6):538-42. PMID: 17919309
  4. Kuchar, L, et al. Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am. J. Med. Genet. A. 2009; 149A(4):613-21. PMID: 19267410
  5. Harzer, K, et al. Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses. Eur. J. Pediatr. 1989; 149(1):31-9. PMID: 2514102
  6. Hulková, H, et al. A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum. Mol. Genet. 2001; 10(9):927-40. PMID: 11309366
  7. Bradová, V, et al. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease. Hum. Genet. 1993; 92(2):143-52. PMID: 8370580
  8. Schulze, H, Sandhoff, K. Lysosomal lipid storage diseases. Cold Spring Harb Perspect Biol. 2011; 3(6):None. PMID: 21502308
  9. Cesani, M, et al. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum. Mutat. 2016; 37(1):16-27. PMID: 26462614

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
PSAP NM_002778.3