Mucolipidosis and Stuttering via the GNPTAB Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4671 GNPTAB$640.00 81479 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
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 26 days.

Clinical Sensitivity

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 mutations in one of the three genes (GNPTAB, GNPTG, and NAGPA). About half of the 25 patients had mutations in GNPTAB.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 GNPTAB$990.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

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Over 100

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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 20 days.

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, 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, Stuttering (also called stammering) is speech that is characterized by frequent repetition and/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).


Mucolipidosis II and III α/β (ML II and ML IIIα/β) are inherited in an autosomal recessive manner and are caused by mutations in GNPTAB, which encodes the enzyme alpha/beta GlcNAc-1-phosphotransferase. ML II mutations 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 mutations are also common in ML IIIα/β, but missense mutations 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). Mutations 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 mutations were reported in stuttering patients. Most patients were heterozygous for the mutations, although a few were homozygous. Penetrance of the mutations does not appear to be complete. Mutations in the GNPTG and NAGPA genes, also involved in the lysosomal enzyme-targeting pathway, were similarly reported in stuttering patients.

Testing Strategy

For this NextGen test, the full coding regions plus ~10 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by 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 pheynotypic 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 and/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).


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

Related Tests

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Fetal Concerns Sequencing Panel with CNV Detection
Mucolipidosis and Stuttering via the GNPTG Gene
Stuttering via the NAGPA Gene


Genetic Counselors
  • Bargal, R., (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., (2010). "Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering." N Engl J Med 362(8): 677-85. PubMed ID: 20147709
  • Krishnakanth, M., (2008). "Clozapine-induced stuttering: a case series." Prim Care Companion J Clin Psychiatry 10(4): 333-4. PubMed ID: 18787667
  • Kudo, M., (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., (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., (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., (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
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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most 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 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.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

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.

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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.
  • 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.
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