Mucopolysaccharidosis Type IIIC / Sanfilippo Syndrome C via the HGSNAT Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7183 HGSNAT 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7183HGSNAT81479 81479(x2) $640 Order Options and Pricing

Pricing Comments

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 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Jana Paderova, PhD

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. MPS IIIC is caused by deficiency of the lysosomal acetyl-CoA:alpha-glucosaminide acetyltransferase.

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 mental retardation. 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).

MPS III occurs in diverse ethnic and geographical populations with an estimated prevalence of 0.87:100,000 per live births (www.orpha.net).

Genetics

MPS IIIC is inherited in an autosomal recessive manner and is caused by mutations in the HGSNAT gene (Hrebicek et al. 2006; Fan et al. 2006). To date, about 65 pathogenic variants have been reported in patients from various ethnic and geographical populations. All major types of variants have been reported including two large deletions (Human Mutation Gene Database and Leiden Open Variation Database).

There are no clear genotype-phenotype correlations in any of the four MPS III because most pathogenic variants are private or occur with low frequencies (Yogalingam and Hopwood 2001). In addition, severity and clinical course vary even among sibs with HGSNAT causative mutations. Nonetheless, patients with two nonsense variants usually develop a severe MPS III (Ruijter et al. 2008; Feldhammer et al. 2009).

The HGSNAT gene encodes acetyl-CoA:alpha-glucosaminide acetyltransferase, one of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate.

Clinical Sensitivity - Sequencing with CNV PG-Select

Using Sanger sequencing, pathogenic variants in the HGSNAT gene were identified in 98% of the mutated alleles in patients with clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of acetyl-CoA:alpha-glucosaminide N-acetyltransferase in leukocytes or cultured skin fibroblasts (Ruijter et al. 2008).

Although rare, large pathogenic deletions in HGSNAT have been reported (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the HGSNAT gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Confirmation of the diagnosis of MPS IIIC in patients with clinical features and radiological findings suggestive of MPS III, increased urinary heparan sulfate excretion, and reduced acetyl-CoA:alpha-glucosaminide acetyltransferase activity; and identification of asymptomatic heterozygous carriers.

Gene

Official Gene Symbol OMIM ID
HGSNAT 610453
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mucopolysaccharidosis, MPS-III-C AR 252930

Related Test

Name
Mucopolysaccharidosis Type III Panel

Citations

  • Fan X, Zhang H, Zhang S, Bagshaw RD, Tropak MB, Callahan JW, Mahuran DJ. 2006. Identification of the Gene Encoding the Enzyme Deficient in Mucopolysaccharidosis IIIC (Sanfilippo Disease Type C). Am J Hum Genet 79: 738–744. PubMed ID: 16960811
  • Feldhammer M, Durand S, Mrázová L, Boucher R-M, Laframboise R, Steinfeld R, Wraith JE, Michelakakis H, Diggelen OP van, Hřebíček M, Kmoch S, Pshezhetsky AV. 2009. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase ( HGSNAT ) gene. Human Mutation 30: 918–925. PubMed ID: 19479962
  • Hrebicek M, Mrazova L, Seyrantepe V, Durand S, Roslin NM, Noskova L, Hartmannova H, Ivanek R, Cizkova A, Poupetova H, Sikora J, Urinovska J, et al. 2006. Mutations in TMEM76 Cause Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome). Am J Hum Genet 79: 807–819. PubMed ID: 17033958
  • Human Gene Mutation Database (Bio-base).
  • Leiden Open Variation Database
  • Neufeld EF, Muenzer J. 2001. The Mucoploysaccharidoses. 136: 3421-3452.
  • Orphanet
  • Ruijter GJG, Valstar MJ, Kamp JM van de, Helm RM van der, Durand S, Diggelen OP van, Wevers RA, Poorthuis BJ, Pshezhetsky AV, Wijburg FA. 2008. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol. Genet. Metab. 93: 104–111. PubMed ID: 18024218
  • Wijburg FA, Wegrzyn G, Burton BK, Tylki-Szymanska A. 2013. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatrica 102: 462–470. PubMed ID: 23336697
  • Yogalingam G, Hopwood JJ. 2001. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum. Mutat. 18: 264–281. PubMed ID: 11668611

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

View Ordering Instructions

1) Select Test Method (Backbone)


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2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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