Huntington Chorea

Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances; onset is usually between 35 and 45 years of age. Early manifestations can include subtle changes in eye movements, coordination, minor involuntary movements, difficulty in mental planning, and a depressed or irritable mood. These evolve into more prominent chorea, with voluntary activity becoming increasingly difficult, and worsening dysarthria and dysphagia. The late stages are characterized by severe motor disability.

HD is caused exclusively by a trinucleotide (CAG) repeat expansion mutation in the HTT gene. The inheritance pattern is autosomal dominant with anticipation. Anticipation is the phenomenon of increased severity or decreased age of onset in successive generation due to expansion of the unstable repeat. In HD, anticipation is generally greater with paternal transmission of the expanded allele.

Alleles in the HTT gene are classified as:

• Normal: < 26 CAG repeats
• Normal (intermediate): 27 to 35 CAG repeats
• HD-causing with reduced penetrance: 36 to 39 repeats
• HD-causing with full penetrance: > 40 repeats

Normal (intermediate) alleles are not disease causing, but may be at risk of expansion into the pathogenic range in subsequent generations.  Alleles of 36-39 repeats show reduced penetrance; an individual with an allele in this range may or may not develop symptoms of Huntington disease during their lifetime.  Expanded alleles >100 repeats have been reported for infantile/juvenile onset HD.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of HD.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at risk of being affected with HD. Samples from both parents may be required to complete the prenatal diagnosis analysis.
3. Presymptomatic testing:
   1. Adults known to be at risk of developing symptoms due to a molecularly confirmed family history. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Sizing of the CAG repeat is performed on an ABI genetic analyzer following fluorescence-based PCR amplification. To aid in interpretation, PCR amplification is also performed to size the adjacent non-pathogenic CCG repeat, and the combined CAG/CCG repeat region. As required, triplet-primed (tp) PCR is performed.

Pregnancy-related/Prenatal

If pregnancy management will be altered, 3 weeks; otherwise, routine TAT.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. 

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

In certain scenarios of repeat size mosaicism, false negative results may occur. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

Rare single nucleotide variants or polymorphisms could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

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