Test Id : SCAP

Specimen preferred to arrive within 96 hours of collection.

Specimen Type: Whole blood

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

• Informed Consent for Genetic Testing
• Molecular Genetics: Neurology Patient Information
• Informed Consent for Genetic Testing (Spanish)

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Neurology Patient Information

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.

0.5 mL

Molecular confirmation of clinically suspected spinocerebellar ataxia when a specific subtype isn’t suspected

This test assesses for CAG repeat expansions within the ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes, associated with spinocerebellar ataxia (SCA) type 1, SCA2, SCA3, SCA6, and SCA7. Additionally, testing for ATXN1 assesses for CAT trinucleotides that interrupt the CAG repeat tract.

Spinocerebellar Ataxia Type 1:

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive ataxia, dysarthria, eventual deterioration of bulbar functions, and ophthalmoplegia. Onset typically occurs in the third to fourth decade of life. Most individuals present with difficulties in gait or slurred speech. SCA1 is caused by an expansion of the CAG (cytosine-adenine-guanine) trinucleotide repeat in the ATXN1 gene. This trinucleotide repeat is polymorphic in the general population, with the number of benign repeats ranging from 6 to 37. The pathogenicity of the repeat is dependent on the presence or absence of CAT (cytosine-adenine-thymine) trinucleotide repeats that interrupt the CAG repeats. Therefore, individuals with 36 to 37 uninterrupted CAG repeats are predisposed to having a child with an expanded allele. In affected individuals, the CAG expansions are greater than 38 uninterrupted CAG repeats or greater than 44 repeats, regardless of the presence or absence of CAT repeat interruptions. The presence of CAT repeats in an individual with 36 to 43 CAG repeats is considered normal and not disease-causing. In contrast, 38 CAG repeats without CAT repeats are of uncertain significance. There is a report of an individual with very last onset SCA1 with 38 CAG repeats. Reduced penetrance has been associated with 44 CAG repeats. As with other trinucleotide repeat disorders, large CAG expansions are associated with earlier onset and a more severe clinical course.

Spinocerebellar Ataxia Type 2:Spinocerebellar ataxia type 2 (SCA2) is characterized by slowly progressive ataxia, dysarthria, and slow saccadic eye movements. The mean age of onset is in the fourth decade, but symptoms may appear from childhood to later adulthood. SCA2 is caused by an expansion of the CAG trinucleotide repeat in the ATXN2 gene. This trinucleotide repeat is polymorphic in the general population, with the number of benign repeats less than 32. However, 29 to 31 heterozygous repeats have been associated with an increased exponential risk for amyotrophic lateral sclerosis (ALS). Additionally, there has been a report of an individual homozygous for 31 repeats with late-onset cerebellar ataxia. In contrast, 27 repeats have been associated with a protective effect for ALS. In affected individuals, the CAG expansion is greater than 34 repeats, with the most common disease-causing alleles having 37 to 39 repeats. Larger CAG expansions are associated with an earlier age of onset but repeat length cannot predict age of onset or disease severity. A CAG expansion of 32 repeats is of unclear clinical significance. Repeats in the 33 to 34 range are associated with reduced penetrance.

Spinocerebellar Ataxia Type 3:

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is characterized by progressive cerebellar ataxia and pyramidal signs. The age of onset is highly variable but most commonly occurs in the second to fifth decade of life. Individuals may present with gait problems, speech difficulties, clumsiness, or visual blurring. SCA3 is caused by an expansion of the CAG trinucleotide repeat in the ATXN3 gene. This trinucleotide repeat is polymorphic in the general population, with the number of benign repeats ranging from 12 to 44. In affected individuals, the CAG expansion ranges from 60 to 87 repeats. A loose correlation exists between repeat length and clinical phenotype. Individuals with 45 to 59 CAG repeats are predisposed to having a child with an expanded allele and may or may not have symptoms themselves. There have been reports of reduced penetrant and nonpenetrant alleles with repeats in this range.

Spinocerebellar Ataxia Type 6:

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The mean age of onset is 43 to 52 years. Initial symptoms include unsteadiness, stumbling, and imbalance. SCA6 is caused by an expansion of the CAG trinucleotide repeat in the CACNA1A gene. This trinucleotide repeat is polymorphic in the general population, with the number of benign repeats less than 19. In affected individuals, the CAG expansion ranges from 20 to 33 repeats. Larger CAG expansions are associated with an earlier age of onset. A CAG expansion of 19 repeats is of unclear clinical significance. Individuals with 19 CAG repeats are predisposed to having a child with an expanded allele. Additionally, homozygous abnormal expansions have been reported in individuals with younger age of onset and a more severe phenotype.

Spinocerebellar Ataxia Type 7:

Spinocerebellar ataxia type 7 (SCA7) is characterized by progressive cerebellar ataxia, including dysarthria and dysphagia, and con-rod and retinal dystrophy. Onset ranges from infancy to the fifth or sixth decade of life. SCA7 is caused by an expansion of the CAG trinucleotide repeat in the ATXN7 gene. This trinucleotide repeat is polymorphic in the general population, with the number of benign repeats less than 19. In affected individuals, the CAG expansion is greater than 36 repeats. A CAG expansion of 19 to 27 repeats is of unclear clinical significance. Individuals with 28 to 33 repeats are predisposed to having a child with an expanded allele but are unlikely to have symptoms themselves. Thirty-four to 36 repeats are associated with reduced penetrance, and when symptoms do occur, they are more likely to be associated with later onset and a milder phenotype.

SPINOCEREBELLAR ATAXIA TYPE 1

Normal alleles: <36 CAG repeats

Normal alleles with CAT interruptions: 36-43 repeats

Intermediate alleles without CAT interruptions: 36-37 repeats

Uncertain significance: 38 repeats

Expanded alleles without CAT interruptions: >38 CAG repeats

Expanded alleles with CAT interruptions: >43 CAG repeats

SPINOCEREBELLAR ATAXIA TYPE 2

Normal alleles: <32 repeats

Uncertain significance: 31 homozygous and 32 repeats

Reduced penetrance: 33-34 repeats

Expanded alleles: >34 repeats

SPINOCEREBELLAR ATAXIA TYPE 3

Normal alleles: <45 repeats

Intermediate alleles: 45-59 repeats

Expanded alleles: >59 repeats

SPINOCEREBELLAR ATAXIA TYPE 6

Normal alleles: <19 repeats

Intermediate alleles: 19 heterozygous repeats

Uncertain significance: 19 homozygous repeats

Expanded alleles: >19 repeats

SPINOCEREBELLAR ATAXIA TYPE 7

Normal alleles: <19 repeats

Uncertain significance: 19-27 repeats

Intermediate alleles: 28-33 repeats

Reduced penetrance: 34-36 repeats

Expanded alleles: >36 repeats

An interpretive report will be provided.

An interpretive report will be provided.

For predictive testing, it is important to first document the presence of a CAG (cytosine-adenine-guanine)-repeat expansion in an affected family member to confirm that the repeat expansion is the underlying mechanism of disease in the family.

It is strongly recommended that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in the interpretation of results may occur if information given is inaccurate or incomplete.

Due to somatic mosaicism, repeat size identified in the peripheral blood specimen may not reflect the repeat size in untested tissues (eg, central nervous system). In addition, a negative result does not rule out the presence of a variant in the mosaic state that may be present but below the limit of detection of this assay (approximately 10%).

Rare sequence variants immediately downstream of the spinocerebellar ataxia repeat regions may interfere with genotype results but are not expected to affect repeat-primed peaks.

Rare undocumented alterations (ie, polymorphisms) in the polymerase-chain reaction primer binding regions may lead to false-negative results.

1. Soong BW, Morrison PJ: Spinocerebellar ataxias. Handb Clin Neurol. 2018;155:143-174. doi: 10.1016/B978-0-444-64189-2.00010-X

2. Buijsen RAM, Toonen LJA, Gardiner SL, van Roon-Mom WMC: Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Neurotherapeutics. 2019 Apr;16(2):263-286. doi: 10.1007/s13311-018-00696-y

A polymerase-chain reaction-based assay is used to amplify across the region of the ATXN1, ATXN2, ATXN3, CACNA1A, or ATXN7 genes containing CAG (cytosine-adenine-guanine) repeats. Additionally, testing assesses for CAT (cytosine-adenine-thymine) trinucleotides that interrupt the CAG repeat tract within the ATXN1 gene.(Unpublished Mayo method)

Monday, Wednesday

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This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

81178

81179

81180

81181

81184

81479 (if appropriate for government payers)