Scientists have developed a new technique for genetic testing that can predict a woman’s risk of having a child with fragile X syndrome when she carries a specific type of mutation.
The study that discusses the method, “Detecting AGG Interruptions in Females With a FMR1 Premutation by Long-Read Single-Molecule Sequencing: A 1 Year Clinical Experience,” was published in the journal Frontiers in Genetics.
Fragile X syndrome is linked to an expansion of three nucleotides — CGG — in the FMR1 gene. Nucleotides are the building blocks of DNA. While a normal gene has about 30 CGG repeats, in fragile X patients, there can be more than 200.
Intermediate cases exist, called premutation carriers, in which the size of the repeat varies between 55 and 200 nucleotides. These cases may show fragile X-associated tremor/ataxia syndrome or fragile X-associated primary ovarian insufficiency, among other disorders.
Women carrying a premutation are at a higher risk of having a child with the disease. However, this risk is influenced by another set of triple nucleotides, the AGG. Women with larger repeats of CGG who carry fewer AGGs are at the highest risk.
According to researchers, “The risk of transmitting a full mutation for a woman with 75 repeats and two AGG triplets is 12%, but this increases to 77% if no AGG interruptions are present,” researchers wrote.
Accounting for these two parameters — a repeat’s length and the number of AGG triplets — is important in genetic counseling to accurately assess a woman’s risk of having a child with the disease to allow her to plan accordingly.
“For example, in case of a small risk a woman might opt for a natural pregnancy followed up by prenatal diagnosis while she might choose for preimplantation genetic diagnosis (PGD) if the risk is high,” researchers wrote.
A PGD involves checking the genes or chromosomes of embryos for a specific genetic condition.
However, while the repeat size is easy to determine, detecting AGG triplets is technically challenging and has limited the use of this parameter in a clinical setting.
To address these technical issues, researchers developed a new methodology that uses a specific type of genetic sequencing to identify AGG triplets in women with an FMR1 premutation.
A total of 51 women were screened with this method at the Center of Human Genetics in Belgium. Fifty patients carried either one normal gene and one intermediate (26 women) or a premutation gene variant (24). Only one woman carried two premutation gene variants.
Thirteen of the 24 women carrying a premutation had a repeat size of 60-84 CGG repeats, and were considered to be the group in which the presence of an AGG triplet would make a bigger impact. Three of the 13 women were found to carry no AGG interruption. As such, their risk of having a child with fragile X syndrome was considered higher than that of other patients.
Two women carried more than 85 CGG repeats and had higher risks: For the woman with 95 repeats and no AGGs, the risk of having a child with fragile X syndrome was 100 percent; for the woman with 89 repeats and two AGGs, it was 60 percent.
In light of these results, the study’s authors believe that assessing AGG triplets in women with a premutation will help them make an informed decision about future pregnancies.