My cousin and I inherited the same bum chromosome. Somewhere back in family history, tiny bits of chromosomes 19 and 22 got swapped (See Who is arm22q13?). I am the proud owner of a hybrid and unhelpful chromosome 22 that causes 22q13 deletion syndrome (See Understanding translocations in 22q13 deletion syndrome: genetics and evolution). My equally unfortunate cousin has the same chromosome. Perhaps her’s is slightly different from mine, but it is not likely very different considering how much we know about its common source. In spite of having the exact same deletion, our children turned out very differently. Both of my kids who received this chromosome were failure to thrive babies. One died and the other one almost died (See photo of David). My cousin had no such experience. Her daughter has 22q13 deletion syndrome, but unlike David, she did not spend 6 years learning to walk, 9 years before oral feeding and she can talk in short sentences. Why has virtually the exact same deletion had such different consequences?
This is the question I am asked the most by other parents of children with 22q13 deletion syndrome. Why does one child with a much larger deletion talk, while another child with a much smaller deletion seem much worse? To be sure, this disparity in phenotype manifestation is very real. It is all around and we should not be swayed by phenotype-genotype deniers, if any exist. The reality of large phenotype variability is important because it address another often asked question. If SHANK3 is not what causes 22q13 deletion syndrome, why is there a child with only a SHANK3 mutation that can’t walk or talk? Of course, other children with only SHANK3 mutations walk and talk, some remarkably well. Once you accept the dilemma that similar deletions can have very different outcomes, this argument for a favorite gene (SHANK3 today, probably some other gene in the future) goes away.
So, how do we explain these dramatic differences? The answer is, there are many answers. There are so many ways that similar deletions can have very different outcomes, that it takes a catalog of explanations to cover them. Here we go.
- Loss of heterozygosity (a.k.a., hemizygosity). Small genetic errors occur all the time during development and in adulthood. Environmental factors from cosmic radiation to infections, sunburn to environmental toxins, can create small errors. Cells have mechanisms to repair errors, but one important hedge against serious genetic errors is the fact that we carry two of every gene (one from mom and one from dad). When a person or a tissue in the body has only one copy of a gene, there is a unique opportunity for uncorrected errors. 22q13 deletion syndrome is the loss of some or many genes on one chromosome. This creates hemizygosity (“half as many copies”) for those genes. Any uncorrected error in the sole remaining gene can have a dramatic effect. Loss of one gene, then damage to the remaining gene is sometimes called a “2nd hit”. The error can be global (whole body and detectable with genetic testing), or it can be local (limited to one small region of the body, or one region of the brain). When it is local, it is undetectable and becomes an unexplained difference.
- Imprinting. Imprinting is when one of the two inherited genes is silenced (turned off). Angelman syndrome is an intellectual disability syndrome with a number of similarities to 22q13 deletion syndrome. It is caused by imprinting that turns off an important gene. Not much is known about how imprinting and chromosomal deletions interact, but obviously it would be a problem if the only remaining copy of a gene was inactivated through imprinting. It would be another unexplained difference.
- Impact of gene mutation. A gene that is completely deleted is often less damaging than a gene that has mutated. That this the story with cancer cells. We would much rather the cancerous cells die than grow with mutated genes. If a chromosomal deletion includes only part of a gene, that gene can start creating proteins that actually interfere with normal cell operation. (See When missing a gene is a good thing.) So, a smaller deletion might disrupt part of a gene. That partial deletion might be big trouble.
- Gene combinations. It is no surprise that single gene mutations/deletions are easier to understand than 22q13 deletion syndrome, where many genes are lost. A lot can happen when multiple genes are involved. The best studied cases are cancer. Cancer occurs when the right (rather, wrong) combination of genes are deleted or mutated. Recent work on autism spectrum disorder and schizophrenia show that these disorders are most often caused when a large number of gene errors add up. Each error contributes in a small way. In some cases, there are a few important genes, but they have little or no impact unless many other genes are also involved. These gene combinations are so subtle and poorly understood, that terms like “genetic background” act as placeholders until we understand more. My cousin’s child and David have practically identical copies of chromosomes 22. The main genetic difference between them come from my cousin’s husband and my wife. Each spouse contributed slight, but very important, differences in their “background” genetics. There is a lot that could be learned about 22q13 deletion syndrome genes from studying families like ours. Many other families could benefit and we could get a clearer picture of the causes of phenotype variations in 22q13 deletion syndrome. So far, no one has asked scientists to embark on such a study.
- Mosaicism and somatic mutations. Recent evidence shows that a genetic error can occur during development in only one small region of the brain. That is, some, perhaps many people have gene mutations that impact only certain areas of the brain. These events might explain many individual variations, including things like learning disabilities. In the case of 22q13 deletion syndrome, these silent mutations are likely to have a much more serious effect as the added mutation may interact with one or more of the 30 to 100+ missing genes. In cases of SHANK3 mutation syndrome, the impact of SHANK3 may be greatly amplified by other lost genes in specific brain regions. Blood tests on these patients may show up as SHANK3 syndrome, but deep in the brain they may have multiple genes lost.
- Genetic regulators (elements). Since 2009 the ENCODE genetics project (https://www.encodeproject.org/) has sought to find the bits and pieces of DNA that regulate genes. Genes make up the smallest part of DNA. Most of DNA is made up of gene regulators. This is very easy to understand when you realize that skin cells, brain cells, intestine cells and liver cells all have exactly the same genes. The difference is which genes are turned on and which are turned off. Skin cells know they are skin cells and only use skin cell genes. The DNA is regulated in each tissue to match the genetic signature necessary to make that tissue. Chromosome 22 deletions not only knock out genes, they knock out genetic regulators. A 4.7 Mbase terminal deletion may not hit any more genes than a 4.8 Mbase deletion, but it may hit crucial regulator sites. It is even possible to hit the regulator site of a missing gene. That site may impact the remaining gene on the unaffected chromosome. Even when researchers do a whole exome sequencing, they miss most of the regulators. Gene regulators are not impossible to detect, but they can be very difficult to notice. They are a likely cause of many unexplained differences.
Given the complexity and many opportunities for unexplained variation, we can begin to appreciate that knowing an individual’s deletion size does not provide all the answers. However, thanks to modern tools, there are ways to study the effects of deletion size even with such wide variability. These tools can be used to tease out which genes contribute to each medical problem. It requires a serious commitment by parents to push researchers and medical staff toward taking full advantage of genetic reports. Too much focus on one favorite gene hampers scientific and medical advancement. Those working on another chromosome deletion syndrome (18q deletion syndrome) have studied their syndrome wisely over the past 50 years. They are turning science into medicine for the suffers of 18q (See Making chromosome abnormalities treatable conditions). The 18q people have developed a road map that the 22q13 deletion syndrome people can easily follow (See Consequences of chromosome 18q deletions). My past blogs have worked hard to make this point, but nothing is more convincing than seeing others take the lead with such clarity and commitment. Why have we not benefited? The only explanation I can find is that the 22q13 deletion syndrome community lacks qualified, unbiased science leadership. It is a fairly obvious problem, with very sad consequences. There are no more treatments for David today than there were 30 years ago. We know which genes are missing and for many of them, we know what they do (See How do we know which genes are important and 22q13 deletion syndrome: the hope of precision medicine). What we don’t seem to know is how to make science work for the benefit of our families.
22q13 deletion syndrome: the hope of precision medicine
How do we know which genes are important
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction