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The “Other” Genetic Test

Fragile-X-infographic-400-square-300x300When 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.

To learn more about fragile X syndrome, visit the National Fragile X Foundation. They have a fantastic infographic about fragile X (part of which is shown at the top of this blog).

August is “SMA Awareness Month”

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In an attempt to express interest in my career, my husband likes to send me interesting links to news stories and videos that relate to genetics. He likes even more to send me links to his fantasy baseball players’ accomplishments. This week was his crowning achievement, as he sent me one that combined genetics and baseball. It was a video and article from ESPN.com about a 6 year old boy and his twin sister, both of whom have spinal muscular atrophy (SMA). The boy’s dream was to play for the Arizona Diamondbacks. The video is incredible and is a real tear-jerker!

If you or your partner has been pregnant in the past few years, you might have heard of SMA since your OB/GYN may have offered you genetic testing for this condition. SMA is an inherited disease of the motor nerves that causes muscle weakness and atrophy (wasting). Motor nerves arise from the spinal cord and control the muscles that are used for activities such as breathing, crawling, walking, head and neck control, and swallowing. So if the motor nerves are not working properly, these bodily functions are compromised.  In his book “Genetic Rounds,” pediatric geneticist Dr. Robert Marion (Einstein) describes SMA as “the childhood equivalent of the better-known, but also poorly understood, amyotrophic lateral sclerosis, more commonly known as Lou Gehrig’s disease…” (pgs 85-86). SMA is a rare disorder occurring in approximately 8 out of every 100,000 live births, and is the leading cause of infant death. There are four types of SMA, which range from lethal in infancy to a less severe form that develops in adulthood.

Like other Ashkenazi Jewish diseases we have talked about on this blog, SMA is inherited in an autosomal recessive pattern. So if both parents in a couple are carriers of SMA, there is a 1 in 4 chance for them to have a child who is affected.

The reason many OB/GYNs order SMA testing is because in 2008, the American College of Medical Genetics and Genomics came out with a Practice Guideline that said: “Because SMA is present in all populations, carrier testing should be offered to all couples regardless of race or ethnicity.” Recent studies have shown that the carrier frequency is about 1 in 56 in the general population, and about 1 in 67 in the Ashkenazi Jewish population.

If you look at our current panel of diseases for screening our Ashkenazi patients, you will see that based on carrier frequency, SMA is actually more common than many of the other diseases on the panel. I would like to point out that even though it is more common, SMA does not fall under the category of “Ashkenazi Jewish genetic diseases.” This is because those conditions have known “founder mutations,” or genetic changes that are frequent in that specific population. SMA mutations are common in ALL populations, not just in Ashkenazi Jews. Since we often see patients who come for Ashkenazi testing before a pregnancy, we recommend that they also get screened for SMA at the same time. This is also true for the Sephardic and non-Jewish patients we see.

August is “SMA Awareness Month.” To learn more about SMA and the research initiatives to treat it, go online to the SMA Foundation website.  Personally, I am made aware of SMA every day since my neighbor is affected with type II SMA and I see her playing outside in her wheelchair all the time. But for those of you who do not know anyone who is affected, try to become aware that this condition exists. Make sure to get screened before a pregnancy or early into one, and spread the word to your child-bearing friends and family. You could really make the difference!

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