Canavan and Tay-Sachs Diseases are both severe neurodegenerative disorders with increased carrier rates in the Ashkenazi Jewish population. Molecular testing for a small number of mutations is highly sensitive in that population, but not in other ethnic groups. Full gene sequence analysis at Ambry Genetics provides a detection rate of 99% across all ethnicities. This enables the greatest possible carrier risk reduction for high-risk or mixed-ethnicity couples, expands options for prenatal diagnosis, simplifies carrier testing in the extended family, and clarifies or confirms biochemical diagnoses.

Canavan Disease results from mutations in the ASPA gene and disruption of myelination of the central nervous system. Onset occurs in infancy with hypotonia, progressive loss of motor control, and macrocephaly. Patients usually do not survive past childhood. The most common mutations account for only about 50% of those found in the non-Ashkenazi Jewish. More than 50 disease-causing mutations, including gross deletions, have been reported. Biochemical carrier testing is not available for screening purposes.

The test is a full gene sequence analysis of ASPA. In addition, gross deletion/duplication analysis of the entire ASPA gene is performed to detect known and potential novel gross deletions.

Tay-Sachs Disease is a lysosomal storage disorder caused by HEXA gene mutations. Most cases are rapidly progressive with infantile onset. Late onset Tay-Sachs with childhood or early adult presentation is caused by HEXA mutations that allow residual Hex A enzyme activity. Enzyme analysis is a sensitive carrier screening and diagnostic tool that should be used in all cases. However, DNA analysis serves as a valuable complement when:

• Carrier screens have indeterminate results
• Approximately 36% of enzymatically-defined non-Ashkenazi Jewish and 2% of Ashkenazi Jewish “carriers” are actually pseudodeficiency mutation carriers with no increased risk for affected children
• Disease variants and mutations in other genes can cause symptoms and mask enzyme abnormalities

Ambry Genetics requires enzyme analysis prior to Tay-Sachs Plus for carrier and diagnostic tests. Full gene sequence analysis can detect the 100+ described HEXA mutations. Together these tests provide the highest possible sensitivity and specificity.

The test is a full gene sequence analysis of HEXA. In addition, the 7.6 kb French-Canadian deletion and two pseudodeficiency mutations are detected.

• Carrier testing for high-risk, anxious, or mixed-ethnicity couples
• Prenatal diagnosis on CVS or amniotic fluid for known carrier couples
• Mutation definition in affected patients
• Resolution of indeterminate or pseudodeficient Tay-Sachs enzyme results
• Diagnostic clarification in patients with Tay-Sachs symptoms and inconsistent enzyme results

The following table shows revised or post-test carrier risks by ethnicity, assuming a negative Ambry Test result and no family history of the disease.

Ethnicity	Canavan Carrier Risk Before Test	Revised Carrier Risk after Canavan AMPLIFIED	Tay-Sachs Carrier Risk Before Test	Revised Carrier Risk after Tay-Sachs Plus*
Ashkenazi Jewish	1/57	1/5601	1/30	1/2901
Other populations at general risk	unknown; <1/57	<1/5601	1/280	1/27,901
Cajun, French-Canadian	unknown; <1/57	<1/5601	1/30	1/2901
Irish American	unknown; <1/57	<1/5601	1/44	1/4301

*Calculation excludes consideration of enzyme analysis results.

 The Ambry Tests: Canavan AMPLIFIED & Tay-Sachs Plus

General Test Information
The Ambry Test: Canavan AMPLIFIED
    (Abobe PDF document)

General Test Information
The Ambry Test: Tay-Sachs Plus
    (Abobe PDF document)

The following CPT Codes for The Ambry Test reflects Ambry Genetics’ interpretation of CPT coding requirements based on AMA guidelines:

Ambry Test: Canavan AMPLIFIED
83891, 83894, 83898, 83900, 83901, 83904, 83909, 83912

Ambry Test: Tay-Sachs Plus
83891, 83894, 83898, 83904, 83909, 83912

CPT codes are provided only as a guide to assist you in billing. CPT coding is the sole responsibility of the billing party.

---

Disclaimer:

This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing.
The Ambry Test: Canavan AMPLIFIED analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, small indels, gross deletions, and gross duplications. It is not intended to analyze the following types of mutations: gross insertions, gene rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: Canavan AMPLIFIED is designed and validated to be capable of detecting about ~99% of Canavan Disease mutations, respectively (considering less than 1% being the other types of mutations). Canavan Disease is a complex clinical disorder, which in the majority of cases is due to alterations in the ASPA gene generally detected by The Ambry Test: Canavan AMPLIFIED except as noted above. Mutations in other genes or the regions not tested by The Ambry Test: Canavan AMPLIFIED can also give rise to clinical conditions similar or identical to Canavan Disease.
The Ambry Test: Tay-Sachs Plus analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions, and small indels and is not intended to analyze the following types of mutations: gross deletions (except the 7.6kb French-Canadian deletion), gross duplications, gross insertions, gene rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: Tay-Sachs Plus is designed and validated to be capable of detecting about ~99% of Tay-Sachs Disease mutations (considering less than 1% to be the other types of mutations). Tay-Sachs Disease is a complex clinical disorder, which in the majority of cases is due to alterations in the HEXA gene generally detected by The Ambry Test: Tay-Sachs Plus except as noted above. Mutations in other genes or the regions not tested by The Ambry Test: Tay-Sachs Plus can also give rise to clinical conditions similar or identical to Tay-Sachs Disease.
Although molecular tests are highly accurate, rare diagnostic errors may occur. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature. References are available upon request.