Genetic screening for fragile X syndrome should be available to all pregnant women and to those considering having a child, regardless of family history or fertility issues, a study suggests.
The study, “Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines,” was published in Molecular Genetics & Genomic Medicine and recently presented at the National Society of Genetic Counselors 38th Annual Conference, in Salt Lake City, Utah.
Fragile X, the most frequent genetic cause of autism, is caused by the expansion of CGG repeats in the FMR1 gene, which provides instructions for making the fragile X mental retardation protein, or FMRP.
While full mutation carriers typically have more than 200 CGG repeats, premutation carriers carry between 55 and 200 CGG repeats. Healthy individuals have fewer than 57 CGG repeats. (Of note, C stands for cytosine and G for guanine, two of the four building blocks of DNA).
“Approximately 1 in 150 women carry an FMR1 premutation that confers risk for [fragile X] in offspring,” wrote the study’s researchers, who are current employees of Myriad Women’s Health, a genetic screening company. “For this reason, many providers believe that FMR1 carrier screening should be offered to all women who are pregnant or considering pregnancy.”
However, current guidelines, including those defined by the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG), recommend genetic screening for select groups: women with a family history of fragile X, individuals with intellectual disability suggesting fragile X or related disorders, or those undergoing fertility tests.
However, many premutation carriers do not have a family history, so these recommendations do not identify all those at risk for pregnancies affected by fragile X. Concerns about patient understanding of inheritance patterns and fragile X manifestations have been among the reasons to resist wider screening.
The researchers addressed such concerns by analyzing reproductive and pregnancy data of 122 women carrying FMR1 premutations, regardless of their eligibility for screening according to current guidelines.
More than half of the women (63%) met current screening criteria, while the remaining (37%) did not. Nearly all women (98%) were followed in a post‐test genetic consultation by a medical provider or genetic counselor.
Of the 73 women (60%) who were screened before conceiving, 54 said they were prepared to take action to lower the risk of having an affected child. These actions included resorting to assisted reproductive treatments (in vitro fertilization with preimplantation genetic testing), undergoing prenatal tests, and opting for adoption instead of having a biological child.
The extent to which couples were prepared or decided to pursue any of these actions was not significantly different in women who reported either family history or fertility evaluation compared with those who did not.
From the 49 women (40%) who were screened prenatally, 20 opted for having prenatal diagnostic tests. Again, the degree to which couples decided to have such testing was similar in women who met screening eligibility criteria (37%) compared to women who did not meet the criteria (31%).
“We found that physicians recommended screening for a substantial number of patients even when they did not meet ACOG or ACMG screening criteria,” the researchers wrote. “Further, half of the patients who did not meet these criteria requested it.”
“Importantly, meeting the criteria had little effect on the extent to which patients acted to reduce the risk of an affected pregnancy, calling into question the value of guidelines and coverage policies restricting screening to only those who meet the criteria,” they said.
“Our study adds support to the expansion of [fragile X] carrier screening to include all women who are pregnant or considering pregnancy,” the team added.
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