Mucolipidosis and Stuttering via the GNPTAB 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
4671 GNPTAB 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4671GNPTAB81479 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

Mucolipidosis II (ML II) (OMIM 252500), also called inclusion-cell or I-cell disease, is part of the lysosomal storage disease family. The disease manifests at birth, and patients typically do not survive past the first 1-2 years. Phenotypic characteristics include thickening of the skin, coarse facial features, hypertrophic gingival, thoracic deformities, clubfoot, kyphosis, hip dislocations, dysostosis multiplex, and cardiac involvements. Death usually occurs due to respiratory insufficiency from stiffening of the thoracic cage (Leroy et al. GeneReviews, 2012, www.genetests.org). ML II can be differentiated from mucolipidosis III alpha/beta (ML III α/β) (OMIM 252600) by earlier clinical onset and more severe phenotypic characteristics.

ML III α/β, also called pseudo-Hurler polydystrophy, manifests clinically at approximately 3 years of age. Phenotypic characteristics include slow growth rate, moderate dysostosis multiplex, joint stiffness, mild coarsening of facial features, mild cognitive impairment. Cardiorespiratory complications are the common cause of death (Leroy et al. GeneReviews, 2012, www.genetests.org).

Stuttering (also called stammering) is speech that is characterized by frequent repetition or prolongation of sounds, syllables, or words or by frequent hesitations or pauses that disrupt the rhythmic flow of speech. Stuttering affects ~1% of the population and has a mean onset around 30 months of age (Yairi et al. J Speech Hear Res 35:782-788, 1992). Stuttering often resolves spontaneously before adulthood, particularly in females. In rare cases stuttering can occur in adulthood as a result of brain injury (Fawcett. CNS Spectrums 10:94-95, 2005) or drug use (Krishnakanth et al. Prim Care Companion J Clin Psychiatry 10:333-334, 2008). Secondary behaviors, such as eye blinking or other involuntary head movements, are not uncommon (Prasee and Kikano. Am Fam Physician 77:1271-1276, 2008).

Genetics

Mucolipidosis II and III α/β (ML II and ML IIIα/β) are inherited in an autosomal recessive manner and are caused by variants in GNPTAB, which encodes the enzyme alpha/beta GlcNAc-1-phosphotransferase. ML II variants mostly result in premature translational termination (or nonsense mediated decay) (Tiede et al. Nat Med 11:1109-1112, 2005; Kudo et al. Am J Hum Genet 78:451-463, 2006; Tappino et al. Mol Genet Metab 93:129-133, 2008; Tappino et al. Hum Mutat 30:E956-973, 2009). Nonsense, frameshift, and splicing variants are also common in ML IIIα/β, but missense variants are more common than in ML II and are mostly localized to the protein recognition domain, leaving the catalytic domain with some residual activity (Bargal et al. Mol Genet Metab 88:359-363, 2006). Variants in GNPTAB have also been associated with stuttering (Kang et al. N Engl J Med 362:677-685, 2010). GNPTAB encodes the α and β subunits of GlcNAc-phosphotransferase, a protein involved in the lysosomal enzyme-targeting pathway. Four GNPTAB missense variants were reported in stuttering patients. Most patients were heterozygous for the variants, although a few were homozygous. Penetrance of the variants does not appear to be complete. Variants in the GNPTG and NAGPA genes, also involved in the lysosomal enzyme-targeting pathway, were similarly reported in stuttering patients.

Clinical Sensitivity - Sequencing with CNV PG-Select

The sensitivity for the GNPTAB sequencing test is >95% for both ML II and ML III α/β. Kang et al. 2010 reported that 25 of 393 stuttering patients (6%) had variants in one of the three genes (GNPTAB, GNPTG, and NAGPA). About half of the 25 patients had variants in GNPTAB.

Testing Strategy

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

Indications for Test

For ML II, patients are candidates for this test if they have phenotypic symptoms common to ML II and show increased hydrolase (β-D-hexosamindase, β-D-glucuronidase, β-D-galactosidase, and α-L-fucosidase) activity and excessive excretion of oligosaccharides (Oss) in the urine. For ML III α/β, patients are candidates for this test if they have phenotypic symptoms common to ML III α/β and show a significant decrease (90-99%) in UDP-N-acetylglucosamine enzyme activity as well as an increase in hydrolase (β-D-hexosamindase, β-D-glucuronidase, β-D-galactosidase, and α-D-mannosidase) activity. Excessive excretion of oligosaccharides (Oss) in the urine may occur but is not always present.

All stuttering patients are candidates for this test, although it is expected that test yield will be higher for patients with a family history of stuttering or speech characterized by more than 4% stuttering dysfluencies, as measured by instruments such as the Stuttering Severity Instrument, 3rd Edition (Riley Stuttering Severity Instrument for Children and Adults. 3rd ed. Los Angeles: Western Psychological Services 1980).

This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GNPTAB.

Gene

Official Gene Symbol OMIM ID
GNPTAB 607840
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Fetal Concerns Panel
Mucolipidosis and Stuttering via the GNPTG Gene

Citations

  • Bargal, R., et.al. (2006). "When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients." Mol Genet Metab 88(4): 359-63. PubMed ID: 16630736
  • Fawcett, R. G. (2005). "Stroke-associated acquired stuttering." CNS Spectr 10(2): 94-5. PubMed ID: 15685118
  • Glyndon D. Riley (1980). "Stuttering Severity Instrument for Children and Adults.".
  • Kang, C., et.al. (2010). "Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering." N Engl J Med 362(8): 677-85. PubMed ID: 20147709
  • Krishnakanth, M., et.al. (2008). "Clozapine-induced stuttering: a case series." Prim Care Companion J Clin Psychiatry 10(4): 333-4. PubMed ID: 18787667
  • Kudo, M., et.al. (2006). "Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene." Am J Hum Genet 78(3): 451-63. PubMed ID: 16465621
  • Prasse, J. E., Kikano, G. E. (2008). "Stuttering: an overview." Am Fam Physician 77(9): 1271-6. PubMed ID: 18540491
  • Tappino, B., et.al. (2008). "An Alu insertion in compound heterozygosity with a microduplication in GNPTAB gene underlies Mucolipidosis II." Mol Genet Metab 93(2): 129-33. PubMed ID: 17964840
  • Tappino, B., et.al. (2009). "Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types IIalpha/beta and IIIalpha/beta in 46 patients." Hum Mutat 30(11): E956-73. PubMed ID: 19634183
  • Tiede, S., et.al. (2005). "Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase." Nat Med 11(10): 1109-12. PubMed ID: 16200072
  • Yairi, E., Ambrose, N. (1992). "Onset of stuttering in preschool children: selected factors." J Speech Hear Res 35(4): 782-8. PubMed ID: 1405533

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

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