Genetic testing is a clinical diagnostic tool often used to search for the underlying cause of a child’s developmental delays, autism, or intellectual disability.
The first diagnostic genetic test for Fragile X syndrome (FXS) involved looking at the X chromosome under a microscope. In the 1970s, it was observed that some males with inherited intellectual disability had an X chromosome that appeared “fragile,” as if the end had broken off. This is actually where the name “Fragile X” originated. This testing was fairly accurate for identifying males with Fragile X syndrome but could not reliably identify females with Fragile X syndrome or premutation carriers.
In the 1990s, genetic testing technologies improved, and the specific gene associated with Fragile X syndrome — FMR1 — was discovered. Since then, highly accurate Fragile X DNA testing has been widely available to identify individuals with all types of repeat expansions within the FMR1 gene.
Recommended genetic testing includes:
- Chromosomal microarray analysis, which looks for extra or missing pieces of genetic material.
- Exome sequencing, which reads through part of a person’s genetic code.
- A specific DNA test for Fragile X syndrome.
Currently, Fragile X testing must be ordered as a separate test since expansions of the FMR1 gene cannot be detected through microarray or exome sequencing.
Two main testing techniques are used when diagnosing Fragile X-associated disorders:
- Polymerase chain reaction (PCR): This technique is able to identify the size of the repetitive section of the FMR1 gene, including CGG repeat numbers in the normal, intermediate, premutation, and full mutation ranges.
- Southern blot analysis: For full mutations, labs generally follow up with a Southern blot analysis to confirm whether the gene is methylated, a chemical change that prevents it from producing its normal protein, known as FMRP.
Testing for AGG interruptions can be done as a separate test and is most relevant as part of carrier testing. AGG analysis is often ordered as a follow-up test when a premutation or intermediate result is reported in women carriers who plan to have children.
Laboratories typically report the number of CGG repeats within the FMR1 gene. For full mutations, they also report the methylation status and the presence of mosaicism if it’s detected. Because Fragile X testing is widely available through many different laboratories, not all lab reports look the same. Additionally, many primary care providers and non-genetics specialists are unfamiliar with interpreting Fragile X lab reports.
Given the complexity of Fragile X inheritance, it is very important that families living with Fragile X-associated disorders meet with a genetic counselor or geneticist to review the meaning of a positive lab report for the individual and his or her extended family.