Mucolipidosis Type IV via the MCOLN1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
519 MCOLN1$940.00 81479 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

This test will detect mutations in ~ 99% of patients with mutations other than the common deletion in the Ashkenazi Jewish population with a clinical diagnosis of MLIV (Schiffmann et al. GeneReviews, 2010).

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Clinical Features

Mucolipidosis Type 4 (MLIV) is a neurodegenerative disorder characterized by neurodevelopmental delay, encephalopathy, ophthalmological anomalies and achlorhydria (Berman et al. J Pediatr 84(4):519-526, 1974; Schiffmann et al. Proc Natl Acad Sci USA 95(3):1207-1212, 1998). Normal lysosomal enzyme activities in the presence of lysosomal inclusions with heterogeneous lipid and protein contents distinguishes MLIV from mucolipidoses types I, II and III (Geer et al. Pediatr Neurol 42(3):223-226, 2010).

Two clinical subtypes of MLIV are recognized based on the age of onset, severity and a number of atypical clinical features.

1) Typical MLIV is the most severe and frequent form of the disease. Symptoms usually begin during the first year of life and include difficulty in speaking and walking as the result of psychomotor developmental delay, spasticity, hypotonia, bilateral corneal opacity, strabismus, retinal degeneration and optic atrophy.  MRI findings include a thin corpus callosum and white matter abnormalities in the early stage of the disease, and cerebellar atrophy later on (Frei et al. Neurology 51(2):565-569, 1998).  Disease progression is generally slow, except for the ophthalmological manifestations which may ultimately lead to blindness (Geer et al., 2010).

2) Atypical MLIV is characterized by later onset, mild symptoms, and dysmorphic features which are usually absent in the typical form and include clinodactyly, partial syndactyly, puffy eyelids and coarse face. Corneal clouding may be absent (Chitayat et al. Am J Med Genet 41(3):313-318, 1991).

MLIV is pan-ethnic. It is however most prevalent in the Ashkenazi Jewish population with a disease prevalence of about 1:40,000 live births and a carrier rate of 0.01 (Bach G et al. Hum Mutat 26(6):591, 2005).


MLIV is inherited in an autosomal recessive manner, and results from mutations in the MCOLN1 gene (Bargal et al. Nat Genet 26(1):118-123, 2000; Bassi et al. Am J Hum Genet 67(5):1110-1120, 2000; Sun et al. Hum Mol Genet 9(17):2471-2478, 2000). To date, about 30 mutations have been reported and include all types, although missense mutations constitute the majority. Two mutations account for about 95% of all mutations detected in the Ashkenazi Jewish population and include a splicing mutation (c.406-2A>G) and a 6.4-kb  deletion (g.511_6943del) that spans the first six exons.

The MCOLN1 gene encodes mucolipin-1 protein, an integral membrane protein and member of the transient potential receptor (TRP) gene family. It is postulated to be involved in the regulation of membrane trafficking of proteins and lipids in the endocytic pathway (LaPlante et al. Biochem Biophys Res Commun 322(4):1384-1391, 2004).

Testing Strategy

This test involves bidirectional DNA Sanger sequencing of all coding exons and splice sites of the MCOLN1 gene. The full coding sequence of each exon plus ~10 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

Children with mild to moderate developmental delay, ophthalmological abnormalities with or without corneal clouding, elevated blood gastrin levels as the result of achlorhydria, and inclusion bodies in skin biopsy; potential heterozygous carriers of a recessive pathogenic MCOLN1; and partners of individuals known to be heterozygous carriers.


Official Gene Symbol OMIM ID
MCOLN1 605248
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Ganglioside Sialidase Deficiency 252650


Genetic Counselors
  • Bach, G. et al. (2005). "The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations." Hum Mutat 26(6):591. PubMed ID: 16287144
  • Bargal, R. et al. (2000). "Identification of the gene causing mucolipidosis type IV." Nat Genet 26(1):118-123. PubMed ID: 10973263
  • Bassi, M.T. et al. (2000). "Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV." Am J Hum Genet 67(5):1110-1120. PubMed ID: 11013137
  • Berman, E.R. et al. (1974). "Congenital corneal clouding with abnormal systemic storage bodies: a new variant of mucolipidosis." J Pediatr  84(4):519-526. PubMed ID: 4365943
  • Chitayat, D. et al. (1991). "Mucolipidosis type IV: clinical manifestations and natural history." Am J Med Genet 41(3):313-318. PubMed ID: 1789285
  • Frei, K.P. et al. (1998). "Mucolipidosis type IV: characteristic MRI findings." Neurology 51(2):565-569. PubMed ID: 9710036
  • Geer, J.S. et al. (2010). "Mucolipidosis type IV: a subtle pediatric neurodegenerative disorder." Pediatr Neurol 42(3):223-226. PubMed ID: 20159435
  • LaPlante, J.M. et al. (2004). "Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV." Biochem Biophys Res Commun 322(4):1384-1391. PubMed ID: 15336987
  • Schiffman, R. et al. (2010). "Mucolipidosis IV." GeneReviews. PubMed ID: 20301393
  • Schiffmann, R. et al. (1998). "Constitutive achlorhydria in mucolipidosis type IV." Proc Natl Acad Sci USA 95(3):1207-1212. PubMed ID: 9448310
  • Sun, M. et al. (2000). "Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel." Hum Mol Genet 9(17):2471-2478. PubMed ID: 11030752
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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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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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