Test Code: 2048

Congenital Disorder of Glycosylation Id: ALG3 Gene Sequencing
Test Code: 2048
Turnaround time: 7 weeks

CONDITION DESCRIPTION

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, and 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.

Two infants with CDG Id were reported to have severe psychomotor delay, hypsarrhythmia, postnatal microcephaly, optic atrophy, iris coloboma, and atrophy of the brain and corpus callosum. Another child was reported with arthrogryposis multiplex congenita, severe psychomotor delay, microcephaly, seizures, and severe vision impairment, but not iris coloboma. Two sibs had severe psychomotor delay, failure to thrive, microcephaly, hypotonia, and seizures. One had significant digestive issues; the other was more neurologically impaired.

Mutations in the ALG3 gene (3q27) cause CDG Id.

For patients with suspected CDG Id, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

References:
• Freeze HH. Congenital disorders of glycosylation: CDG-I, CDG-II, and beyond. Curr Mol Med 2007; 7:389-396.
• GeneTests: Congenital Disorders of Glycosylation Overview
• Jaeken J, Matthijs G. Congenital disorders of glycosylation: A rapidly expanding disease family. Annu Rev Genomics Hum Genet 2007;8:261- 278.

GENES
ALG3

INDICATIONS
This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of CDG Id Carrier testing in adults with a family history of CDG Id

METHODOLOGY

PCR amplification of 9 exons contained in the ALG3 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.

DETECTION

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 biochemical phenotype.

Analytical Sensitivity: ~99%

SPECIMEN REQUIREMENTS

Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood

Type: Whole Blood
Specimen Requirements:
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.

Type: Saliva
Specimen Requirements:
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.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed by another third party provider, please submit a copy of the sequencing report with the test requisition.

RELATED TESTS

• Deletion/duplication analysis of the ALG3 gene by CGH array is available for those individuals in whom sequence analysis is negative.
• Analysis of other CDG genes is also available.
• Custom diagnostic mutation analysis (test code: 6875) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.