Our esteemed Medical Advisory Board offers their coordinated point of view to help us understand what this means for all of us.  The goal of this letter is to inform parents, provide perspective and look to the future.  These are VERY exciting times, but remember these are early days -- so, Stay Tuned!

Dear SSSA Families: 

Recently, a large Japanese research group published a report saying they found a gene associated with Sotos syndrome. Many of you asked us to comment on this discovery. We welcome this new development and look forward to learning more about the gene as it is studied by other groups. 

1. Kurotaki and his colleagues reported that a gene called NSD1 (Nuclear SET Domain 1)is associated with Sotos Syndrome. This was published in Nature Genetics 30:365-366 in April, 2002. The key to their success was the discovery of a Japanese girl with classic Sotos syndrome who had a chromosome rearrangement. This child had a "balanced" translocation which involved chromosomes 5 and 8. These two chromosomes had become tangled together and part of chromosome 8 ended up on chromosome 5, while part of chromosome 5 ended up on chromosome 8. The "breakpoints" where the chromosomes got rearranged were on the long arms, known as 5q35 and 8q24. As many of you know, other people with Sotos (or suspected Sotos) have had translocations. It could be that, in these other people, the Sotos is unrelated to the translocation. Or it could be that more than one gene change can cause Sotos. These researchers looked very closely at the breakpoints where the chromosomes were fused. What they discovered, using molecular genetic detective work, was that a known gene with the initials NSD-1 was split in two by this rearrangement. Having found this candidate gene, they studied 41 more Japanese people with Sotos syndrome. Twenty of these people were missing a small segment of chromosome 5 which contained the NSD-1 gene. In four others, they found smaller changes within the NSD1 gene which made it malfunction. They concluded that if a person is missing one copy of the gene, or if one of the person's two NSD1 genes is disabled, Sotos will result. The scientific term for this is "haploinsufficiency." 
   
2. The question is whether this NSD1 gene in the 5q35 region is THE Sotos gene. As we all know, there are some Sotos syndrome children who look almost like carbon copies of each other. And then, there are other children we think have Sotos syndrome, even though they don't have the exact appearance. Finally, we know that some children who have been called "Sotos" probably have something else. From what we have seen, we think there is a good chance that the NSD1 gene accounts for most of classic Sotos patients. There is always a possibility that some classic patients will not have deletions or mutations in NSD1. We suspect that the patients who are not typical will not have the NSD1 deletion, but it is possible that some will. Finally, as research continues, it is likely that some Sotos syndrome patients will have a different genetic alteration on a different chromosome. 
   
3. The next question is probably, "When can we start testing our children for this?" But, first, some background information about the process by which a single genetic discovery is confirmed (or disproved). Usually, the first thing that happens is that another group will perform the same experiment to validate this group's results. This is extremely important. Dr Cole and Dr. Naz Rahman are already conducting molecular research in a larger group of UK children with typical Sotos syndrome. They are also studying patients with atypical Sotos syndrome (i.e., other less distinct cases of overgrowth disorders), other recognized overgrowth disorders and familial cases of Sotos syndrome (which are uncommon). The scope of their research will be enormously helpful to understanding Sotos syndrome. Assuming that other groups find the same deletion, then it is quite likely that a test will become available. Usually, genetic testing is offered first as a research test, without charge. Later, the technique gets developed into a fee for service test. This is the sort of test that a commercial lab or university lab would develop. 
   
4. Genetic research is sloooooooow. Finding the gene is the first step. Next, researchers will try to understand the gene function, how it affects Sotos children, and what other activities it is involved in. Scientists now know that a person with only one copy of the gene is likely to have Sotos. They will explore whether there is any connection to possible risk of cancer (which we currently believe is extremely low). 
   
5. We can anticipate your ultimate question: "Can researchers use this information to make my child healthier? Can you improve my child's development?" Rest assured that your goal is our goal, too. But, we have a long way to go before we will be able to consider the idea of therapy. Still, we can certainly expect that research will continue at a steady pace. Sotos syndrome is common enough to make research feasible. And a lot of people who live with and care for children with Sotos will be making sure the process moves forward. A word of caution. Research discoveries often seem "sudden" because the announcements can come out of the blue. But what we don't see are the years of false starts and hard work which preceded the announcements. In reality, progress is made in starts and stops. We have to expect some of each.
   

We will keep you aware of new developments. 

Best wishes, 

Angela Lin, MD

Rebecca Anderson, JD, MS 

Trevor Cole, MD 

Bradley Schaefer, MD

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