Mucopolysaccharidosis Type III Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3419 GNS 81479,81479 Order Options and Pricing
HGSNAT 81479,81479
NAGLU 81479,81479
SGSH 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3419Genes x (4)81479 81479 $640 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

The mucopolysaccharidoses (MPS) are a group of inherited disorders caused by defects in lysosomal enzymes responsible for the stepwise degradation of glycosaminoglycans (GAGs). Each enzyme deficiency results in progressive storage of distinct GAGs in multiple organ systems and subsequent abnormalities. Although MPS share several symptoms, including physical and mental developmental abnormalities, they may differ even within the same enzyme deficiency. Seven clinically distinct types can be recognized (Types I, II, III, IV, VI, VII, and IX). Based on the biochemical and genetic defects, MPS III and IV are further divided in four and two subtypes, respectively. Deficiencies in eleven enzymes have been implicated in the various MPS. Mucopolysaccharidosis Type III, also known as Sanfilippo syndrome is caused by deficiency in any of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate. Enzyme deficiencies result in progressive storage of heparan sulfate primarily in the central nervous system, leading to severe neurodegeneration and developmental delay. MPSIII is classified into four subtypes (MPS IIIA to D) on the basis of the specific enzyme deficiency. The different subtypes are caused by deficiency of: N-sulfoglucosamine sulfohydrolase, also known as sulfaminidase (MPS IIIA); α-N-acetylglucosaminidase (MPS IIIB); heparan acetyl CoA: α-glucosaminide N-acetylglucosaminidase (MPS IIIC); or N-acetylglucosamine 6-sulfatase (MPS IIID). A putative fifth subtype, MPS IIIE, has been proposed to be caused by deficiency of N-glucosamine 3-O-sulfatase, although to date this subtype has only been observed in dog and animal models, with no human cases reported (Fedele 2015). Clinically, MPS III is distinguished from the other MPS by a severe cognitive and neurological impairment; and mild somatic signs. The characteristic features are similar in all four subtypes, although MPS IIIA is usually associated with an earlier age of onset and a faster progression compared to the other MPS. Symptoms appear during childhood and death usually occurs by the second or third decade of life. Symptoms typically begin with episodes of hyperactivity and aggressive behavior and progress to severe behavioral and sleep disturbances, speech difficulties, hearing and visual defects, and intellectual disability. Somatic involvement is variable. Symptoms include mildly coarse facial features, recurrent ear and respiratory infections, scoliosis, hip dysplasia, carpal tunnel syndrome and cardiac valve disease (Neufeld and Muenzer 2001; Wijburg et al. 2013; Fedele 2015). There is currently no treatment for MPS III (Fedele 2015). MPS III occurs in diverse ethnic and geographical populations with an estimated prevalence of 1-9:100,000 live births (www.orpha.net; Fedele 2015).

Genetics

MPS III is inherited in an autosomal recessive manner and is caused by pathogenic variants in one of four genes: SGSH (MPS IIIA; N-sulfoglucosamine sulfohydrolase or sulfaminidase); NAGLU (MPS IIIB; α-N-acetylglucosaminidase); HGSNAT (MPS IIIC; heparan acetyl CoA: α-glucosaminide N-acetylglucosaminidase) or GNS (MGS IIID; N-acetylglucosamine 6-sulfatase) (Fedele, 2015). Pathogenic variants are most common in SGSH and NAGLU with over 100 disease-causing variants in each gene reported in patients from various ethnic and geographical populations, while variants in HGSNAT and GNS have been reported in 66 and 23 patients, respectively. In SGSH, NAGLU, and HGSNAT, most reported variants are missense, although nonsense, splicing, small insertions or deletions and large deletions have been reported. In GNS, the reported variants are evenly distributed across the different variant types (Human Gene Mutation Database; Fedele 2015).

Several studies have reported genotype-phenotype correlations in some subtypes of MPS III. In particular, the following SGSH variants have been associated with a severe phenotype: p.Arg245His; p.Gln380Arg; p.Ser66Trp; c.1080delC (p.Val361Serfs*52); and p.Arg74Cys, while p.Ser298Pro has been associated with an attenuated phenotype (Bodamer et al. 2014; Fedele 2015). In NAGLU, p.Arg297Ter has been associated with a severe phenotype while p.Arg643Cys has been associated in an attenuated phenotype (Bodamer et al. 2014).

See individual gene test descriptions for information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants were identified in SGSH in >98% of the alleles in patients diagnosed with MPS IIIA based on deficient N-sulfoglucosamine sulfohydrolase activity (Valstar et al. 2010a). Pathogenic variants in NAGLU were identified in 94% to 100% of the alleles in patients diagnosed with MPS IIIB based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of alpha-N-acetyl-glucosaminidase activity (Zhao et al. 1998; Beesley et al. 2005). Pathogenic variants in the HGSNAT gene were identified in 98% of the alleles in patients diagnosed with MPS IIIC based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of acetyl-CoA:α-glucosaminide N-acetyltransferase (Ruijter et al. 2008). Finally, pathogenic variants in the GNS gene were identified in approximately 85% of the alleles in patients diagnosed with MPS IIID based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of N-acetylglucosamine-6-sulfatase. Large deletions were identified in all of the remaining alleles (Valstar et al. 2010b).

Although rare, large pathogenic deletions have been reported in all four of the genes associated with Mucopolysaccharidosis Type III (SGSH, NAGLU, HGSNAT, and GNS) (Fedele 2015; Human Gene Mutation Database).

Testing Strategy

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.

Indications for Test

Indications for this test include: confirmation of the diagnosis of MPS III in patients with clinical features and radiological findings suggestive of MPS III, including increased heparan sulfate excretion in urine, and reduced heparan N-sulfatase activity; and identification of asymptomatic heterozygous carriers.

Genes

Official Gene Symbol OMIM ID
GNS 607664
HGSNAT 610453
NAGLU 609701
SGSH 605270
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Beesley C.E et al. 2005. Journal of Inherited Metabolic Disease. 28: 759-67. PubMed ID: 16151907
  • Bodamer O.A. et al. 2014. Molecular Genetics and Metabolism. 113: 34-41. PubMed ID: 25127543
  • Fedele A.O. 2015. The Application of Clinical Genetics. 8: 269-81. PubMed ID: 26648750
  • Human Gene Mutation Database (Bio-base).
  • Neufeld E.F., Muenzer J. 2001. The Mucoploysaccharidoses. 136: 3421-3452.
  • Orphanet
  • Ruijter G.J et al. 2008. Molecular Genetics and Metabolism. 93:104-11. PubMed ID: 18024218
  • Valstar M.J. et al. 2010a. Annals of Neurology. 68: 876-87. PubMed ID: 21061399
  • Valstar MJ et al. 2010b. Human Mutation. 31: E1348-60. PubMed ID: 20232353
  • Wijburg F.A. et al. 2013. Acta Paediatrica. 102: 462-70. PubMed ID: 23336697
  • Zhao H.G. et al. 1998. American Journal of Human Genetics. 62: 53-63. PubMed ID: 9443875

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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