Huntington Disease

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Gene Symbol:  HTT      
       
Chromosomal Locus: 4p16.3 
 
Protein:  huntington 
 
Pseudonyms: HD, Huntington chorea, chorea, ataxia,
 
TURNAROUND TIME:     10 days
 
 2012 AMA Code:81400
 
TESTING METHODOLOGY:
Precise characterization of the expanded CAG trinucleotide repeat of the HTT gene by polymerase chain reaction (PCR) and fluorescent capillary electrophoresis utilizing an internal standard and allelic ladder.
 
SPECIMEN REQUIREMENTS:
  • Collect:Prefer two 5ml whole blood EDTA (lavender top) tube. 
  • Min. Collection: 0.7 ml whole blood EDTA.
  • Transport: blood EDTA at Room Temp shipped next day air (No Saturday delivery; store specimen refrigerated and ship Monday).
  • Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
  • Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.        
  • Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask.  Maternal blood sample is required for maternal cell contamination studies.
A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 to obtain further information.
Counseling and informed consent are recommended for genetic testing and are required for predictive testing. A Center for Genetic Testing at Saint Francis HD consent form is available.
 
SPECIAL TESTING CONSIDERATIONS:
HD is a progressive neurodegenerative disorder with a lethal outcome; therefore a unique testing protocol is followed as the standard of care for predictive testing.
(1) For symptomatic individuals, testing is ordered by the patient care giver.
(2) For minors, predictive testing is discouraged and testing should only be pursued for diagnostic reasons.
(3) For predictive testing, a patient requests enrollment in a Presymptomatic Program involving education, genetic counseling, waiting periods, special informed consent and involvement of psychological support.
Note: For predictive testing, it is important to first document the presence of a CAG-repeat expansion in the HTT gene in an affected family member to confirm that the molecular expansion is the underlying mechanism of disease in the family.
 
INTERPRETATIVE DATA:
 
Incidence: 7 in 100,000.
 
Inheritance: Autosomal dominant.  Variable age of onset but complete penetrance.
 
Disease Characteristics:
 
The mean age of onset for HD is 35 to 44. Two-thirds of affected individuals first present with subtle neurological changes such as poor coordination, restlessness or repetitive, minor involuntary movements. In others psychiatric changes such as depression or irritabilty precede the neurological ones. During this phase the affected individual can often lead a relatively normal life.
Progression in disease is marked by involuntary choreic movements become severe and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years. Once the involuntary neurological symptoms start affecting autonomic muscle systems death occurs rapidly.  The size of the CAG repeat region dictates the age of onset and the speed of the progression of symptoms rather than the actual spectrum of symptoms.
 
Molecular Genetic Mechanism: Normal and clinically unaffected individuals have a range of 5 to 35 CAG repeats (the amino acid glutamine) in the N terminus of the gene. However, although individuals with a range of 27 to 35 CAG repeats will show no symptoms, the DNA region may be unstable and result in an abnormal expansion to 39 or more repeats in their offspring. Expansions with a range of 36 to 39 repeats lead to a progressively higher incidence of expression and at 40 repeats and greater the disease will be fully penetrant.
Juvenile onset of Huntington disease has an expansion of >60 CAG repeats. Increase in the CAG repeats often increases with each generation (genetic anticipation) and is most common in father-to-child inheritance; consequently an earlier onset of disease is also observed. The actual mechanism by which the repeats cause symptoms is still under debate.
 
ReferenceRanges:
  • Normal alleles:  6 to 26 CAG repeats
  • Mutable Normal Alleles: 27 to 35 CAG repeats
  • Reduced Penetrance Abnormal Alleles:  36 to 39 CAG repeats
  • Fully Penetrant Abnormal Alleles: > 40  CAG repeats
Related Tests: SCA screenDRPLA, FRDA and Neurological Panel 
 
Clinical Sensitivity: 99%
 
Analytical Sensitivity: 99%
 
Test Limitations:  This test examines the CAG repeat region of the N terminus, exclusively. However, no other mechanism has been described for HD and the test is considered diagnostic.
 
INDICATIONS FOR USE:
  • Individuals with a family history of HD who want to determine their true risk.
  • Families considering future medical and disability insurance needs.
  • Prenatal diagnosis for individuals at risk
  • To differentiate individuals with HD from other ataxias.
ADDITIONAL RESOURCES:
OMIM – Huntington Disease:  http://omim.org/entry/143100
GeneReviews:http://www.ncbi.nlm.nih.gov/books/NBK1305/