Mucopolysaccharidosis Type II via the IDS Gene
- Summary and Pricing
- Clinical Features and Genetics
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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; Coutinho et al. 2012 ). See also the National MPS Society at www.mpssociety.org.
MPS II, also called Hunter syndrome, is an X-linked recessive disorder caused by deficiency in the lysosomal iduronate sulfatase and subsequent accumulation of dermatan sulfate and heparin sulfate in several organ systems, resulting in a wide range of symptoms. MPS II is characterized by a great heterogeneity in regard to age of onset, severity and clinical course. Symptoms usually begin between 18 months and 4 years of age. In the most severe cases, death occurs by the second decade of life as the result of cardio-respiratory complications. Patients with the attenuated form live into adulthood. Typical symptoms include coarse facial features, short stature, stiff joint, thick bones, skeletal deformities, claw-hand deformity, skin lesions, airway obstruction, hearing loss, hepatosplenomagaly, cardiomyopathy, learning difficulties, and neurological decline. In contrast to MPS I, there is no corneal clouding in MPS II (Neufeld and Muenzer 2001; Wraith et al. 2008; Scarpa 2011).
MPS II occurs in diverse ethnic and geographical populations, with an estimated prevalence of 0.6 in 100,000 male live births (Orphanet, www.orpha.net).
Although rare, affected female carriers have been reported (Tuschl et al. 2005; Guillén-Navarro et al. 2013).
Defects in the IDS gene (which is located on the X chromosome) are responsible for iduronate sulfatase deficiency and subsequent development of MPS II (Mossman et al. 1983). More than 500 causative variants have been reported. Most types of variants have been detected, including de novo mutations in sporadic male patients (Froissart et al. 1998). Total or partial deletions of the IDS gene represent ~8% of the catalogued mutations; and complex rearrangements represent ~ 3% of the mutations (Human Gene Mutation Database).
Although heterozygous female carriers are usually asymptomatic, Hunter disease has been reported in rare female cases as the result of skewed X-chromosome inactivation alone (Sukegawa et al. 1998) or in combination with de novo mutations on the paternal chromosome, or as the result of a homozygous mutation that led to mildly affected, undiagnosed male patients in consanguineous families (Cudry et al. 2000).
There are no clear genotype-phenotype correlations because most pathogenic variants are private. In addition, point mutations may result in a wide range of phenotypes, with the same mutation leading to different phenotypes even among siblings (Vafiadaki et al. 1998). Nonetheless, large deletions, which account for about 17% of patients, appear to result in a severe phenotype (Wraith et al. 2008).
The IDS gene encodes iduronate sulfatase, which catalyzes the first step of the degradation of dermatan and heparan sulfates.
This test involves bidirectional DNA sequencing of all coding exons and splice sites of the IDS 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 II in patients, including males and rare females (Tuschl et al. 2005) with clinical features and radiological findings suggestive of MPS such as increased urinary dermatan and heparin sulfate excretion, and reduced iduronate sulfatase; and identification of asymptomatic heterozygous female carriers.
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- Genetic Counselor Team - firstname.lastname@example.org
- Khemissa Bejaoui, PhD - email@example.com
- Brusius-Facchin AC, Schwartz IVD, Zimmer C, Ribeiro MG, Acosta AX, Horovitz D, Monlleó IL, Fontes MIB, Fett-Conte A, Sobrinho RPO, Duarte AR, Boy R, et al. 2014. Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients. Mol. Genet. Metab. 111: 133–138. PubMed ID: 24125893
- Coutinho MF, Lacerda L, Alves S. 2012. Glycosaminoglycan Storage Disorders: A Review. Biochemistry Research International 2012: 1–16. PubMed ID: 22013531
- Cudry S, Tigaud I, Froissart R, Bonnet V, Maire I, Bozon D. 2000. MPS II in females: molecular basis of two different cases. J. Med. Genet. 37: E29. PubMed ID: 11015461
- Froissart R, Maire I, Millat G, Cudry S, Birot AM, Bonnet V, Bouton O, Bozon D. 1998. Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin. Genet. 53: 362–368. PubMed ID: 9660053
- Guillén-Navarro E, Domingo-Jiménez MR, Alcalde-Martín C, Cancho-Candela R, Couce ML, Galán-Gómez E, Alonso-Luengo O. 2013. Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study. Orphanet J Rare Dis 8: 92. PubMed ID: 23800320
- Human Gene Mutation Database (Bio-base).
- Mossman J, Blunt S, Stephens R, Jones EE, Pembrey M. 1983. Hunter’s disease in a girl: association with X:5 chromosomal translocation disrupting the Hunter gene. Arch Dis Child 58: 911–915. PubMed ID: 6418082
- Neufeld EF, Muenzer J. 2001. The Mucoploysaccharidoses. 136: 3421-3452.
- Scarpa M. 2011. Mucopolysaccharidosis Type II. 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: 20301451
- Sukegawa K, Matsuzaki T, Fukuda S, Masuno M, Fukao T, Kokuryu M, Iwata S, Tomatsu S, Orii T, Kondo N. 1998. Brother/sister siblings affected with Hunter disease: evidence for skewed X chromosome inactivation. Clin. Genet. 53: 96–101. PubMed ID: 9611068
- Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. 2005. Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr. Neurol. 32: 270–272. PubMed ID: 15797184
- Vafiadaki E, Cooper A, Heptinstall L, Hatton C, Thornley M, Wraith J. 1998. Mutation analysis in 57 unrelated patients with MPS II (Hunter’s disease). Arch Dis Child 79: 237–241. PubMed ID: 9875019
- Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J, HOS Investigators. 2008. Initial report from the Hunter Outcome Survey. Genet. Med. 10: 508–516. PubMed ID: 18580692
- Wraith JE, Scarpa M, Beck M, Bodamer OA, Meirleir L De, Guffon N, Meldgaard Lund A, Malm G, Ploeg AT Van der, Zeman J. 2008. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur. J. Pediatr. 167: 267–277. PubMed ID: 18038146
Bi-Directional Sanger Sequencing
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.
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).
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.
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- 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.
- 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.
(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.
(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.
(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.