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Mucopolysaccharidosis Type I via the IDUA Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
452 IDUA$870.00 81406 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Using Sanger sequencing, pathogenic variants in the IDUA gene were identified in about 97% of alleles in patients biochemically proven to have MPS I (Beesley et al. 2001).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 IDUA$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity
Thus far, large pathogenic deletions in the IDUA gene have not been reported (Human Mutation Gene Database).

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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 (Neufeld and Muenzer 2001). See also the National MPS Society at (www.mpssociety.org).

MPS I is a multisystemic disorder caused by deficiency in lysosomal alpha-L-iduronidase and subsequent systemic accumulation of dermatan and heparan sulfates. Historically, three major clinical subtypes are recognized on the basis of the age of onset, severity and disease course (Neufeld and Muenzer 2001; Clarke and Heppner 2011; Coutinho et al. 2012).

1) Hurler syndrome is the most severe and frequent form of MPS I. It is characterized by onset in infancy and death by the first decade of life, as the result of heart or lung failure. Symptoms include coarse facial features, corneal clouding, hydrocephalus, heart disease, respiratory difficulties, hepatosplenomegaly, joint stiffness, learning disabilities, and mental retardation.

2) Hurler-Scheie syndrome is characterized by onset in childhood and intermediate severity, progressive somatic involvement with normal intelligence and survival to adulthood.

3) Scheie syndrome is the mildest and most heterogeneous form. Symptoms appear after the age of five years and include stiff joint and heart disease. Life span is usually normal (Thomas et al. 2010).

Due to the wide range of clinical manifestations and the lack of clear delineation between the three subtypes, patients are best described as having severe and attenuated forms of MPS I disease (Neufeld and Muenzer 2001).

MPS I affects people worldwide with an estimated prevalence of 1:100,000 per live births (www.orpha.net).
Genetics
MPS I is inherited in an autosomal recessive manner and results from pathogenic variants in the IDUA gene (Scott et al. 1992; Lee-Chen et al. 1999; Moskowitz et al. 1993). Over 200 causative variants have been reported in patients from various ethnic and geographical populations and include missense, nonsense, splicing, small insertions or deletions and indels. Large pathogenic deletions in the IDUA gene have not been reported (Human Mutation Gene Database). 

There are no clear genotype-phenotype correlations because most pathogenic variants are private or occur with low frequencies. Nonetheless, patients with a nonsense mutation on both alleles typically develop a severe clinical phenotype (Terlato and Cox GF 2003). In addition, genetic and other modifying factors may contribute to the clinical phenotype (Clarke et al. 1994)

The IDUA gene encodes the lysosomal alpha-L-iduronidase enzyme, which hydrolyzes the terminal a-L-iduronic acid residues of dermatan sulfate and heparan sulfate.
Testing Strategy
This test involves bidirectional DNA sequencing of all coding exons and splice sites of the IDUA gene. The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
Confirmation of the diagnosis of MPS I in patients with clinical features and radiological findings suggestive of MPS such as increased urinary dermatan and heparin sulfate excretion, and reduced alpha-L-iduronidase activity; and identification of asymptomatic heterozygous carriers.

Gene

Official Gene Symbol OMIM ID
IDUA 252800
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Beesley CE, Meaney CA, Greenland G, Adams V, Vellodi A, Young EP, Winchester BG. 2001. Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. Hum. Genet. 109: 503–511. PubMed ID: 11735025
  • Clarke LA, Heppner J. 2011. Mucopolysaccharidosis Type I. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301341
  • Clarke LA, Nelson PV, Warrington CL, Morris CP, Hopwood JJ, Scott HS. 1994. Mutation analysis of 19 North American mucopolysaccharidosis type I patients: identification of two additional frequent mutations. Human mutation 3: 275–282. PubMed ID: 8019563
  • Coutinho MF, Lacerda L, Alves S. 2012. Glycosaminoglycan Storage Disorders: A Review. Biochemistry Research International 2012: 1–16. PubMed ID: 22013531
  • Human Gene Mutation Database (Bio-base).
  • Lee-Chen GJ, Lin SP, Tang YF, Chin YW. 1999. Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity. Clin. Genet. 56: 66–70. PubMed ID: 10466419
  • Moskowitz SM, Tieu PT, Neufeld EF. 1993. Mutation in Scheie syndrome (MPS IS): a G-->A transition creates new splice site in intron 5 of one IDUA allele. Hum. Mutat. 2: 141–144. PubMed ID: 8318992
  • Neufeld EF, Muenzer J. 2001. The Mucoploysaccharidoses. 136: 3421-3452.
  • Orphanet
  • Scott HS, Litjens T, Hopwood JJ, Morris CP. 1992. A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. Hum. Mutat. 1: 103–108. PubMed ID: 1301196
  • Terlato NJ, Cox GF. 2003. Can mucopolysaccharidosis type I disease severity be predicted based on a patient’s genotype? A comprehensive review of the literature: Genetics in Medicine 5: 286–294. PubMed ID: 12865757
  • Thomas JA, Beck M, Clarke JTR, Cox GF. 2010. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. Journal of Inherited Metabolic Disease 33: 421–427. PubMed ID: 20532982
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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