Advances in Huntington's disease diagnostics: development of a standard reference material
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Published on: February 27, 2018
Barbara C Levin1, Kristy L Richie, John P Jakupciak
1National Institute of Standards & Technology, 100 Bureau Drive, Mail Stop 8311, Biochemical Science Division, Chemical Science & Technology Laboratory, Gaithersburg, MD 20899-8311, USA. barbara.levin@nist.gov
Insights
Huntington's disease (HD) is a genetic neurodegenerative disorder. Standardizing CAG repeat testing with reference materials ensures accurate diagnosis for at-risk individuals.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder.
- It is characterized by choreic movements, cognitive decline, and psychiatric changes, typically with onset in middle age.
- HD is caused by an expanded CAG trinucleotide repeat in the HD gene on chromosome 4.
Purpose of the Study:
- To highlight the need for standardized methodology in determining CAG repeat numbers for Huntington's disease (HD) testing.
- To emphasize the importance of accurate genetic testing for predictive and prenatal diagnosis.
- To introduce the development of a standard reference material for HD testing.
Main Methods:
- Review of current diagnostic criteria for Huntington's disease.
- Analysis of CAG trinucleotide repeat expansion in the HD gene.
- Discussion of the development of standard reference materials by the National Institute of Standards and Technology.
Main Results:
- Targeted mutational analysis for CAG repeats is highly sensitive (>99%) for diagnosing HD.
- Specific CAG repeat ranges correlate with disease presence, risk, and potential inheritance.
- A standard reference material is being developed to ensure consistent and accurate laboratory testing.
Conclusions:
- Standardization of CAG repeat determination is crucial for reliable Huntington's disease diagnosis.
- The development of a National Institute of Standards and Technology standard reference material will enhance quality control in clinical laboratories.
- Accurate and comparable testing is essential for at-risk individuals undergoing predictive or prenatal screening.
Abstract:
Huntington's disease (HD) is a neurodegenerative disease that affects four to seven individuals per 100,000. The onset of symptoms usually begins in middle age, although approximately 5% become symptomatic as juveniles. Death occurs approximately 15 years following the onset of symptoms, which include choreic movements, cognitive decline and psychiatric changes. HD is an autosomal dominant inherited disease that is associated with an expansion of a trinucleotide (CAG) repeat located on chromosome 4. Physicians rely on a positive family history, and diagnostic and genetic tests to detect the expansion in the number of CAG trinucleotide repeats in the HD gene to confirm the diagnosis. More than 99% of HD patients have 40 or more CAG triplet repeats and, therefore, targeted mutational analysis is greater than 99% sensitive. Individuals with 26 triplet repeats or less are normal, and while those with 27-35 repeats may not demonstrate symptoms themselves, their offspring may have the disease. Individuals with 36-39 repeats may or may not exhibit symptoms. The College of American Pathology/American College of Medical Genetics Biochemical and Molecular Genetics Resource Committee has emphasized the need to standardize the methodology for the determination of the accurate number of CAG repeats. This will prevent false-positive or -negative results when conducting predictive or prenatal testing of at-risk individuals. The National Institute of Standards and Technology is developing a standard reference material to provide these positive and negative controls needed by clinical testing laboratories. The use of a HD standard reference material will provide the quality control and assurance that data from different laboratories are both comparable and accurate.
