Test Code: 5950

Congenital Disorder of Glycosylation Is: ALG13 Gene Deletion/Duplication
Test Code: 5950
Turnaround time: 3 weeks

CONDITION DESCRIPTION

Congenital disorders of glycosylation (CDG) are a group of mostly 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.

Timal et al. (2012) identified a hemizygous de novo pathogenic variant in the ALG13 gene (Xq23) in an individual with CDG-Is. His features included epilepsy, hepatomegaly, recurrent infections, swelling, microcephaly, and bilateral optic nerve atrophy. The same pathogenic variant, also de novo, was identified by the Epi4K Consortium in an unrelated female with seizures and severe intellectual disability.

References:

  • Epi4K Consortium. (2013), Nature, 501:217-221.
  • Timal et al. (2012), Hum Mol Genet, 21:4151-4161.
  • OMIM #300776: ALG13 gene
  • OMIM #300884: CDG-Is

GENES
ALG13

INDICATIONS
This test is indicated for:
• Confirmation of a clinical diagnosis of CDG-Is in an individual in whom sequence analysis was negative.
• Carrier testing in adults with a family history of CDG-Is in whom sequence analysis was negative.

METHODOLOGY
DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

Please note that a “backbone” of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off- target copy number variants causative of disease may be identified that may or may not be related to the patient’s phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.

DETECTION

Detection is limited to duplications and deletions. The CGH array will not detect point or intronic pathogenic variants. Results of molecular analysis must be interpreted in the context of the patient’s clinical and/or biochemical phenotype.

SPECIMEN REQUIREMENTS

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: Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

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

• Sequence analysis of the ALG13 gene is available and is required before deletion/duplication analysis.
• 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.