Congenital Disorder of Glycosylation Ir: DDOST Gene Sequencing
Test Code: 3821
Turnaround time: 5 weeks
Congenital disorders of glycosylation (CDG) are a group of autosomal recessive genetic disorders caused by the alteration in synthesis and structure of protein and lipid glycosylation. In the past decade, over 30 genetic diseases have been identified that alter glycan synthesis, structure and ultimately the function of nearly all organ systems.
CDG type I (CDGI) disorders result from impaired synthesis of the incomplete lipid linked oligosaccharide (LLO) and/or its attachment to the growing polypeptide chain. CDG-Ia is the most common form reported, due to phosphomannomutase deficiency, an enzyme that converts mannose-6- phosphate to mannose-1-phosphate. CDG-Ib (phosphomannose isomerase, MPI deficiency) is the only known treatable form, by giving mannose orally. CDG type II (CDGII) includes defects in processing of N-glycans.
Phenotypes of this disorder are extremely variable. Manifestations range from severe developmental delay and hypotonia with multiple organ system involvement beginning in infancy, to hypoglycemia and protein-losing enteropathy with normal development. Most subtypes have been described in only a few individuals, however, thus understanding of the phenotypes is limited.
The current diagnostic test for CDG is analysis of serum transferrin glycoforms, also called “transferrin isoforms analysis,” or “carbohydrate-deficient transferrin analysis.” If positive, this testing can be followed by DNA testing to identify mutations in the gene involved.
Jones et al. (2012) identified two mutations in the DDOST gene (1p36.1) in an individual with features of CDG but who had tested negative for 25 genes known to be associated with CDG.
• Jones et al. (2012) Am J Hum Genet, 90:363-368.
• OMIM #602202: DDOST gene
• OMIM #614507: CDG Ir
This test is indicated for:
- Confirmation of a clinical diagnosis of congenital disorder of glycosylation type Ir.
- Carrier testing in adults with a family history of congenital disorder of glycosylation type Ir.
PCR amplification of 11 exons contained in the DDOST gene is performed on the patient’s genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient’s gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.
Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient’s clinical and/or biochemical phenotype.
Analytical Sensitivity: ~99%
Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood
Type: Whole Blood
In EDTA (purple top) or ACD (yellow top) tube: Infants (2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
OrageneTM Saliva Collection kit (available through CEN4GEN) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
Special Instructions: Submit copies of diagnostic biochemical test results with the sample, if appropriate.
• Individual full gene sequencing and deletion duplication analysis are available for many CDG-associated genes.
• CDG Next Generation sequencing panels are available and are organized by comprehensive, multiple glycosylation, N-Glycosylation and Type I.
• Individual deletion/duplication analysis is available for other CDG-associated genes, as well as deletion/duplication panels.
• Custom diagnostic mutation analysis (test code: 6875) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.