Congenital Disorders of Glycosylation, Type IIj via the COG4 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
1453 COG4$1100.00 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
Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all reported causative mutations thus far are detectable by sequencing.

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Clinical Features
Congenital disorders of glycosylation (CDGs) are a group of heterogeneous disorders due to a defect in the linkage of oligosaccharides to proteins. This process involves covalent attachment of carbohydrate chains to the amide group of asparagine (N-glycoprotein) or less commonly to the hydroxyl group of serine/threonine (O-glycoprotein). Congenital disorders of glycosylation result in a wide variety of clinical features due to multisystem involvement, and include defects in nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency (Sparks and Krasnewich 2014; Scott et al. 2014) .

Thus far, only two patients with CDG IIj (COG-CDG) have been described. Onset occurs before one year of age with failure to thrive in infancy. The first patient with CDG IIj presented at 4 months of age with fever, irritability, and complex seizures after vaccination (Reynders et al. 2009). He also exhibited axial hypotonia, peripheral hypotonia, and hyperreflexia along with mild dysmorphic features such as down-sloping frontal area and thick hair. This patient also developed recurrent respiratory infections. By 3 years of age he had microcephaly, cerebral atrophy, ataxia, absence of speech, and psychomotor retardation. A second patient presented at 11 months of age with failure to thrive, recurrent diarrhea, and recurrent respiratory and gastrointestinal infections with sepsis (Ng et al. 2011). Other features included developmental delay, hypotonia, nystagmus, hepatosplenomegaly, and poor growth. Seizures developed at 16 months and an infection was ultimately fatal around 2 years of age. Both patients showed deficiencies in sialylation and galactosylation.
All CDGs exhibit autosomal recessive inheritance. More than 40 genes have been found to be involved with CDGs, but the majority of these have only been reported in a small number of individual patients (Sparks and Krasnewich 2014). The COG4 gene encodes a subunit of the conserved oligomeric Golgi (COG) complex which is composed of eight subunits. It functions as a vesicular tether during retrograde Golgi trafficking which is important for the recycling of Golgi resident proteins (such as glycosylation enzymes) that are essential for the proper glycosylation of secretory proteins (Willett et al. 2013). Defects in COG subunits that lead to aberrant glycosylation are likely a result of abnormal transport or distribution of glycosylation enzymes. Patients with COG4 pathogenic variants are considered to present with a milder phenotype in comparison to the other COG gene deficiencies (Reynders et al. 2009). Missense variants, a nonsense variant, and a small deletion are thus far the only pathogenic variants reported.
Testing Strategy
Testing involves PCR amplification from genomic DNA and bidirectional Sanger sequencing of the 19 coding exons in the COG4 gene and ~10bp of adjacent noncoding sequences. This testing strategy will reveal coding sequence changes, splice site mutations and small insertions or deletions in the COG4 gene, but will not detect large duplications or deletions of the COG4 locus. 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
Candidates for this test are patients with biochemical findings and/or clinical symptoms consistent with CDG IIj; specifically, a transferrin isoform analysis suggestive of CDG type II. Testing is also indicated for family members of patients who have known COG4 pathogenic variants.


Official Gene Symbol OMIM ID
COG4 606976
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Congenital Disorder Of Glycosylation, Type IIj 613489


Genetic Counselors
  • Ng BG, Sharma V, Sun L, Loh E, Hong W, Tay SKH, Freeze HH. 2011. Identification of the first COG-CDG patient of Indian origin. Mol. Genet. Metab. 102: 364–367. PubMed ID: 21185756
  • Reynders E, Foulquier F, Leão Teles E, Quelhas D, Morelle W, Rabouille C, Annaert W, Matthijs G. 2009. Golgi function and dysfunction in the first COG4-deficient CDG type II patient. Hum. Mol. Genet. 18: 3244–3256. PubMed ID: 19494034
  • Scott K, Gadomski T, Kozicz T, Morava E. 2014. Congenital disorders of glycosylation: new defects and still counting. J. Inherit. Metab. Dis. 37: 609-617. PubMed ID: 24831587
  • Sparks SE, Krasnewich DM. 2014. Congenital Disorders of N-linked Glycosylation Pathway Overview. 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: 20301507
  • Willett R, Ungar D, Lupashin V. 2013. The Golgi puppet master: COG complex at center stage of membrane trafficking interactions. Histochemistry and Cell Biology 140: 271–283. PubMed ID: 23839779
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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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