Test Code: 9540

Homocystinuria: CBS Gene Sequencing
Test Code: 9540
Turnaround time: 5 weeks


Homocystinuria is an autosomal recessive disorder resulting from a deficiency of the enzyme cystathionine beta-synthase (CBS). Laboratory findings include markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine beta-synthase (CBS) enzyme activity.

The disease presents with findings that can range from multiple organ disease beginning in infancy or early childhood to only thromboembolism expressed in early to middle adult years. The major findings in classic homocystinuria include developmental delay and mental retardation, ectopia lentis and/or severe myopia, skeletal abnormalities, vascular abnormalities such as thromboembolism, and clinical similarities to Marfan syndrome. Expressivity is variable for all of the clinical signs. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is typically, but not always, milder than the non-responsive variant. The mean IQ of affected individuals with B6-responsiveness is 79 versus 57 for those who are B6 non responsive. Thromboembolism is the major cause of early death and morbidity. Other features that may occur include seizures, psychiatric problems, extrapyramidal signs such as dystonia, hypopigmentation, pancreatitis, malar flush, and livedo reticularis.

Homocystinuria is caused by mutations in the CBS gene (21q22.3). Sequencing of the CBS gene is recommended after a biochemical diagnosis of homocystinuria, 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: 4305).


• GeneReviews Clinical Summary


This test is indicated for:

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


PCR amplification of 23 exons contained in the CBS 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: It is estimated that sequencing will detect >95% of mutations in the CBS gene. 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
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.

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.


  • Custom Diagnostic Mutation Analysis (test code: 6875) is available to family members if mutations are identified by sequencing.
  • A Deletion/Duplication Assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition for more information.