Argininosuccinate Lyase Deficiency: ASL Gene Sequencing
Test Code: 3829
Turnaround time: 5 weeks
Argininosuccinate lyase deficiency (ASL deficiency) is an autosomal recessive disorder of the urea cycle caused by mutations in the ASL gene (7cen- q11.2). Urea cycle disorders are characterized by hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency, carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia, ASL deficiency, and arginase deficiency.
Two forms of ASL deficiency have been recognized: an early-onset, or malignant, type and a late-onset type. Onset of symptoms of early-onset argininosuccinic aciduria occurs in the first weeks of life. Features include mental and physical retardation, convulsions, episodic unconsciousness, liver enlargement, skin lesions, and dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red. The late-onset type of ASL deficiency is characterized by residual enzyme activity as measured by the incorporation of C-14-citrulline into proteins. Symptoms include relatively mild clinical symptoms, variable age of onset, marked argininosuccinic aciduria, and severe, but not complete, deficiency of argininosuccinate lyase. Early treatment of partial argininosuccinate lyase deficiency with arginine supplementation can result in normal intellectual and psychomotor development.
Sequencing of the ASL gene is recommended after a biochemical analysis consistent with ASL deficiency, and provides a complementary method to confirm the presence of mutations in a proband, identify carriers among the proband’s relatives, and provide prenatal diagnosis in families with known mutations.
For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (test code: 7544).
This test is indicated for:
- Confirmation of a clinical/biochemical diagnosis of ASL deficiency.
- Carrier testing in adults with a family history of ASL deficiency.
PCR amplification of 16 exons contained in the ASL gene is performed on patient genomic DNA. Direct sequencing of amplification products is performed in both the forward and reverse directions using automated fluorescence dideoxy sequencing methods. Patient gene sequences are compared to a normal reference sequence. Sequence variations are then 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. Large deletions are not detected by this analysis.
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%
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.
Submit copies of diagnostic biochemical test results with the sample. 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.
• Ornithine transcarbamylase deficiency gene sequencing (test code: 5518).
• Citrullinemia gene sequencing (test code: 9945).
• Custom diagnostic mutation analysis (test code: 6875) is available to family members if mutations are identified by sequencing.