Bringing Awareness to Fragile X

It seems like every cause has a national day or month to bring awareness to it.  There's even a National Talk like a Pirate Day (September 19th, in case you were interested).  While some of these can be a bit ridiculous, many are actually worthwhile.  This July we're here to tell you about one that's near and dear to our genetics-loving hearts: fragile X awareness month.

Fragile X syndrome is the most common cause of inherited intellectual disability and is also the most common genetic cause of autism.  Symptoms of fragile X syndrome can include mild to moderate intellectual disability, behavioral issues like attention deficits and autism, and characteristic facial features.  When females have fragile X syndrome, they typically are more mildly affected than males.  If you’re interested in learning more about fragile X, the National Fragile X Foundation provides some great information.

 Diagram of fragile x inheritance.

So how is fragile X syndrome inherited?  Good question.  Fragile X syndrome is inherited in a way we call X-linked. This is just a fancy way of saying that the gene that causes it is located on the X chromosome.  Here’s a throwback to high school biology: males are XY, and females are XX.  It is females’ extra, backup copy of the X chromosome that makes them on average less severely affected than males. It gets more complicated though.  Within that gene on the X chromosome an expansion of DNA can cause the gene to function improperly.

What exactly do we mean by expansion of DNA?  To answer that question, you first need to know a little bit more about the gene that causes fragile X.  In this gene, the letters CGG are repeated over and over.  Usually people have 44 or fewer of these repeats.  When our bodies create new cells, like egg or sperm, DNA from an old cell is copied.  Unfortunately our bodies are not perfect though, and mistakes happen.  Copying repeated DNA can be especially tricky, so sometimes these CGG repeats are copied too many times and grow in number.  In fragile X, when there are over 200 repeats, the gene gets turned off and no protein is made, causing the symptoms of fragile X. 

So 44 or less is normal and 200 or more puts someone at risk for fragile X syndrome, but what about the size range between 45 and 199? Most repeat sizes in this range are called a premutation.  Premutations seem to be the tipping point where copying errors become more frequent.  At this size, the repeats have the possibility to expand to over 200 repeats and lead to fragile X syndrome in a woman’s children.  Hence why we call it a ‘pre’-mutation. (Geneticists sure are a creative bunch, aren’t they?)  To make this whole repeat expansion thing even more complicated, we know that repeats in the premutation category are more likely to expand when they are passed from a woman to her children and are unlikely to expand when they are passed from a man.  Because of this, females are at risk to have an affected child, while males are at risk to have daughters who are premutation carriers.

Speaking of premutations, people who carry one of these may develop health concerns other than fragile X syndrome.  One of these health issues is a neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome, or FXTAS.  FXTAS typically affects older, male premutation carriers and leads to symptoms such as tremors, balance problems, and cognitive decline.  And female premutation carriers aren’t completely off the hook either.  Female premutation carriers are at an increased risk for Fragile X-associated primary ovarian insufficiency.  Basically this means improperly functioning ovaries and symptoms similar to early menopause (think hot flashes, irregular periods, and potential infertility).

Carrier screening for Fragile X syndrome is available to any woman who requests it.  Carrier screening is a blood test that can tell if a couple is at increased risk to have children with fragile X syndrome or other conditions (for example, cystic fibrosis or sickle cell disease).  At Insight Medical Genetics, we offer fragile X carrier screening along with a panel of 75 other conditions routinely to all pregnant women and couples considering pregnancy in the near future.  It's possible to be a carrier for any of these conditions and not have any family history.  In fact, of those who are at risk, most have no idea that these conditions run in their families. If you're interested in finding out if you are a carrier of fragile X or any of these other conditions, we recommend that you speak with a genetic counselor in your area.  He or she will be able to give you the information you need to help navigate the sometimes overwhelming waters of genetic testing.