trinucleotide repeat expansion
Some regions of DNA contain a short three-letter motif, such as CAG or CGG, repeated over and over like a word stuttered many times: CAG-CAG-CAG and so on. Usually the number of repeats stays within a safe range. A trinucleotide repeat expansion is what happens when that number grows abnormally large from one generation to the next, crossing a threshold beyond which it causes disease.
These repeats are unstable: when DNA is copied, the repeated unit can slip and be miscounted, adding extra copies. Once a tract becomes long, it tends to grow even more readily, which is why expansions can lengthen as they pass through a family. How an expansion causes harm varies: it may make a toxic protein (as in Huntington disease's CAG repeat), or it may silence a gene or produce a toxic RNA (as in fragile X syndrome's CGG repeat).
Trinucleotide repeat expansions underlie a whole family of disorders, including Huntington disease, fragile X syndrome, myotonic dystrophy and several inherited ataxias. Because the repeat tends to lengthen across generations, these diseases often show anticipation, appearing earlier or more severely in later generations.
A lab measures the CAG repeat in a patient's HTT gene and finds 17 on one copy (normal) and 45 on the other (expanded), explaining the diagnosis and how it can lengthen further in offspring.
The diagnosis hinges on counting repeats and comparing them to a threshold.
The location of the repeat matters: an expansion inside the protein-coding part tends to make a toxic protein, while one in a regulatory or untranslated region more often silences the gene or makes a harmful RNA.