Repeat expansions are a type of genetic mutation responsible for over 40 inherited neurological conditions. These disorders arise from abnormal increases in specific DNA sequences within an individual’s genes, leading to serious health problems, primarily affecting the nervous system.
What Are Repeat Expansions?
DNA, the blueprint for our bodies, consists of four chemical “letters”: A, T, G, and C. These letters arrange into specific sequences that form genes, guiding protein production. Some DNA regions contain short sequences repeated multiple times. These repetitive segments are known as short tandem repeats or microsatellites.
In a repeat expansion, the number of these repeated DNA sequences increases beyond a healthy threshold. For instance, a trinucleotide repeat (three letters) might normally repeat 10 times in a gene. If this sequence expands to 50 or 100 repeats, it can become unstable and disrupt function. These expansions can occur during DNA replication or repair, where the repetitive DNA causes copying machinery to slip, leading to extra copies.
How Repeat Expansions Cause Disease
Expanded repeat sequences can disrupt cell function through various mechanisms. One way involves the production of a toxic protein. If the expanded repeat occurs within a gene’s protein-coding region, it can be translated into an abnormally long, dysfunctional protein that can accumulate. For example, in Huntington disease, an expanded CAG repeat leads to a huntingtin protein with an extended stretch of glutamine, which becomes toxic.
Another mechanism is RNA toxicity, where the expanded repeat in the RNA molecule forms abnormal structures. These abnormal RNA molecules can interfere with cellular processes by trapping or altering the function of important RNA-binding proteins. This disruption can lead to defects in how other genes are processed and expressed, as seen in myotonic dystrophy.
A third mechanism involves transcriptional silencing, where the repeat expansion prevents a gene from being expressed. This can happen if the expansion occurs in a region that controls gene activity, leading to chemical changes that turn the gene off. Without the gene being expressed, the cell cannot produce an essential protein, leading to a loss of function, as observed in Fragile X Syndrome.
Common Diseases Caused by Repeat Expansions
Repeat expansions are linked to a range of neurodegenerative and neuromuscular conditions. Huntington disease, for instance, is caused by an expanded CAG trinucleotide repeat in the HTT gene. This leads to progressive deterioration of nerve cells in the brain, resulting in uncontrolled movements, cognitive decline, and psychiatric symptoms. The number of CAG repeats correlates with the age of disease onset and severity, with more repeats generally leading to earlier and more severe symptoms.
Fragile X Syndrome, a leading cause of inherited intellectual disability, results from an expanded CGG repeat in the FMR1 gene located on the X chromosome. Individuals with this syndrome typically have over 200 CGG repeats, which leads to the silencing of the FMR1 gene and a lack of the FMR1 protein. Normal individuals typically have fewer than 45 CGG repeats.
Myotonic Dystrophy, the most common form of muscular dystrophy in adults, is caused by an expanded CTG repeat in the DMPK gene (Type 1) or a CCTG repeat in the ZNF9 gene (Type 2). This expansion results in muscle weakness, prolonged muscle contractions (myotonia), and affects multiple body systems including the heart, eyes, and brain. Unaffected individuals typically have 5-35 CTG repeats, while those with Myotonic Dystrophy Type 1 can have hundreds to thousands of repeats.
Various Spinocerebellar Ataxias (SCAs) are also linked to repeat expansions, often involving CAG repeats in different genes such as ATXN1, ATXN2, ATXN3, ATXN7, and CACNA1A. These disorders primarily affect the cerebellum, the part of the brain controlling coordination, leading to progressive problems with balance, movement, and speech. The specific SCA type and severity depend on the gene involved and the length of the expansion.
Inheritance and Variability
Repeat expansion disorders show unique inheritance patterns. A notable phenomenon is “anticipation,” where symptoms tend to appear at an earlier age and often become more severe in successive generations. This occurs because the expanded repeat sequences often continue to grow in length when passed from parent to child, particularly during the formation of reproductive cells.
Individuals can carry a “premutation,” which is an expanded repeat that is longer than normal but typically does not cause the full disease. For instance, in Fragile X Syndrome, a premutation might involve 55-200 CGG repeats, whereas a full mutation has over 200 repeats. These premutations are unstable and carry an increased risk of expanding into a full mutation when transmitted to offspring, especially from mothers.
Even within the same family, individuals with the same repeat expansion can experience different symptoms or disease severity, known as clinical variability. This can be influenced by the exact length of the repeat, which can vary between cells in the same person (somatic instability), and other genetic or environmental factors. For example, in some SCAs, additional interruptions within the repeat sequence can alter the clinical presentation.
Diagnosing Repeat Expansion Disorders
Diagnosing repeat expansion disorders typically involves specialized genetic testing. A blood sample is usually collected to analyze the DNA. Laboratory tests, often using techniques like polymerase chain reaction (PCR) or Southern blot analysis, measure the precise number of repeats in specific genes associated with these conditions.
Due to the unique nature of these expansions, standard DNA sequencing methods may not always be effective in detecting them. Newer technologies, such as improved bioinformatics systems for whole-genome sequencing and long-read sequencing, are being developed to overcome these diagnostic challenges. Genetic counseling is an important part of the diagnostic process, helping individuals and families understand the inheritance patterns and implications of these conditions.