Invitae Comprehensive Mucopolysaccharidoses (MPS) Panel

• Mucopolysaccharidoses (MPS)
  • MPS I (Hurler syndrome)
  • MPS II (Hunter syndrome)
  • MPS III (Sanfilipo syndrome)
  • MPS IV (Morquio syndrome)
  • MPS VI (Maroteaux Lamy)
  • MPS VII (Sly syndrome)
  • MPS IX (Natowicz syndrome)

The mucopolysaccharidoses are a constellation of diseases caused by the deficiency of a specific lysosomal enzyme involved in the breakdown of complex sugar and protein molecules known as glycosaminoglycans (GAGs, previously called mucopolysaccharides). Specifically, the breakdown of one or more of the following GAGs is disrupted in each MPS: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS) and/or hyaluronan. Consequently, these substances accumulate in the lysosomes of various tissues resulting in deterioration and degeneration of multiple organs. There is phenotypic variability amongst and within the MPSs, but in general, extensive somatic involvement affecting the heart, lungs, bones, joints and gastrointestinal systems is observed in most MPSs and central nervous system involvement is seen in in types I, II, III and VII. There is a clinical spectrum within each MPS ranging from severe, early onset forms to milder, attenuated forms. Reduced life expectancy is observed in virtually all of the MPSs.

Treatment options, including hematopoietic stem-cell transplant and enzyme replacement therapy, are available for some forms of MPS. Early diagnosis may help slow disease progression and alleviate some symptoms.

Abnormal biochemical studies may include increased urinary GAG levels and reduced enzymatic activity of the enzyme specific to each MPS.

• MPS I: For patients with clinical symptoms of MPS I, sequence variants in the gene IDUA are identified in 95%-97% of patients. Deletions/duplications in this gene are rare.
• MPS II: Pathogenic variants in the IDS gene are the only known cause of mucopolysaccharidosis type II (PMID: 25345092). Among individuals with a confirmed clinical diagnosis of MPS II, 82% have sequence variants and 9% have exonic deletions/duplications, which are both detected in this assay. Another 9% of individuals have complex structural rearrangements that are not identified in this assay (PMID: 20301451).
• MPS III: For individuals with a clinical diagnosis of MPS III approximately 60% will have a pathogenic variant in the SGSH gene, 30% in NAGLU, 4% in HGSNAT and 6% in GNS.
• MPS IV: GALNS is the only gene known to be associated with MPS IV. However, due to the rarity of this condition, the percent of MPS IV attributed to pathogenic variants in GALNS is currently unknown.
• MPS VI: ARSB is the only gene known to be associated with MPS VI. However, due to the rarity of this condition, the percent of MPS VI attributed to pathogenic variants in ARSB is currently unknown.
• MPS VII: GUSB is the only gene known to be associated with MPS VII. However, due to the rarity of this condition, the percent of MPS VII attributed to pathogenic variants in GUSB is currently unknown.
• MPS IX: HYAL1 is the only gene known to be associated with MPS IX. However, due to the rarity of this condition, the percent of MPS IX attributed to pathogenic variants in HYAL1 is currently unknown.

The MPSs are inherited in an autosomal recessive fashion, except for MPSII. MPSII is X-linked.

Collectively the MPSs have an overall incidence of greater than 1:25,000 births.

Individual incidence figures for the different forms of MPS are listed here:

This test is appropriate for any individual with any combination of clinical features consistent with a MPS including: coarse facial features, skeletal deformities, progressive mental retardation, inguinal and umbilical hernias, hepatosplenomegaly, recurrent ear and respiratory infections and or corneal clouding.