When people inquire about how many diseases are on our Ashkenazi panel, we tell them that we currently offer screening for 18 conditions that are distinctly Ashkenazi , plus another two that are common in all populations. I have already blogged about spinal muscular atrophy, the first of those “extras”. Today I want to review why screening for the other one, fragile X syndrome, is more complex.
Fragile X syndrome is the most common inherited form of mental retardation in boys. Affected individuals demonstrate varying degrees of intellectual and behavioral disability, sensory disorders, connective tissue problems, and physical features. About 1 in 250 women are carriers of fragile X syndrome.
When we offer fragile X screening in our clinic, we find that some patients decline. This is because fragile X carrier screening is not the same as screening for the other 19 autosomal recessive conditions. Why?
Firstly, fragile X syndrome is not recessive; it is X-linked. In the context of pre-conception screening for the next generation, only females are screened for fragile X syndrome. If you are a carrier of an X- linked disease, you are at risk to have an affected child, regardless of your partner’s results. Therefore, finding out that you a carrier of an X- linked disease may have a more significant impact than finding out you are a carrier of a recessive disease.
Secondly, fragile X carriers may have certain health issues. While we usually tell our patients that being a carrier has no impact on your health, this may not be true of fragile X carriers. Female premutation carriers have a 20-30% risk of developing “primary ovarian insufficiency.” This condition may lead to infertility and/or early menopause. Male premutation carriers have a 30-40% risk for Fragile X Associated Tremor/Ataxia syndrome (FXTAS), which is often compared to Parkinson’s disease. Female fragile X carriers can develop FXTAS as well (~8% risk), however it is more common in males. So while carriers will not develop fragile X syndrome, they may at risk to develop other medical conditions. Some people want to learn more about their own health risks, while others come in to learn about their offspring only.
Finally, fragile X screening results may not be as simple as “carrier” or “non-carrier”. I am not going to go into a detailed lesson about the fragile X mutation in this blog, but the take home message is that one may be identified as an “intermediate carrier,” which is basically a pre-carrier. This person is not a carrier, so her child will most likely not be affected with fragile X. But the mutation may change over time, causing generations down the line to become true carriers ( what we call “premutation carriers”). Some patients are confused as how to proceed with prenatal or preconception genetic testing when they learn they are intermediate carriers.
So you can see why fragile X screening is not so simple. Currently, the American College of Medical Genetics and Genomics only recommends screening women for fragile X if there is a family history of it or any other form of mental retardation, or if the patient asks for it. There is no doubt that getting screened may be helpful for family planning purposes, but it may come with a price tag of more information than you had initially wanted.