How can the same deletion have such different consequences?

David at 3 days of age: David’s deletion size is exactly the same as his cousin’s, yet the deletion had more severe consequences.

Originally posted 19 January 2016
Updated 19 July 2021
Available in Portuguese  http://pmsbrasil.org.br/como-a-mesma-delecao-pode-ter-consequencias-tao-diferentes/

Introduction

There is a common question among parents of children with 22q13 deletion syndrome. Why is one child with a larger deletion able to talk, while another child with a much smaller deletion nonverbal? Unexplained differences in “phenotype ” (the manifestations of the disorder) can be confusing to parents. Some parents conclude that deletion size is unimportant, but that is incorrect. A sports a team can have good days and bad days. The team is judged on its overall record. Genetics are similar. A deletion in one individual can be more or less impactful, but it is the overall statistics of deletions that demonstrates the clear effect of deletion size.

The person-to-person variation is especially striking when we look at how the same genetic arrangement can have very different outcomes. My cousin and I inherited the same abnormal chromosome. Somewhere back in family history, tiny bits of chromosomes 19 and 22 got swapped (see Who is arm22q13?). My genetics include a hybrid and unhelpful chromosome 22 that has caused 22q13 deletion syndrome in my children (see Understanding translocations in 22q13 deletion syndrome: genetics and evolution). My equally unfortunate cousin had the same chromosome inherited from our grandfather. Despite inheriting 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 a few days after birth and the other one almost died (see photo of David, who lived). My cousin had no such experience. Her daughter has 22q13 deletion syndrome, but without perinatal problems. Her daughter’s case of PMS is not as severe as David’s. For example, David does not talk at all but his cousin talks in short sentences. Why has virtually the exact same deletion had such different consequences? The effect is called phenotype variability.

Phenotype variability even occurs within the SHANK3 gene. Two people with the same pathogenic variant can differ vastly in their ability to walk or talk. Once we accept the dilemma that similar deletions can have very different outcomes, we are in the right frame of mind to try understanding this phenomenon.

Explaining variation

So, how do we explain these dramatic differences? The answer is: there are many answers. There are so many ways similar deletions can have very different outcomes, that it takes a catalog of explanations to cover them. Here we go.

1. 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 an unfortunate opportunity for errors to go uncorrected. 22q13 deletion syndrome is the loss of some or many genes on one chromosome. This creates hemizygosity (“half as many copies”) of 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.
2. 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.
3. Impact of a rare gene variant or partial deletion of a gene. A gene that is completely deleted can be less damaging than a gene that has an abnormal sequence of nucleotides (called a variant). An example of a dangerous variant is when a gene mutation produces cancer. Exposure to too much sun or other carcinogen leads to cells with damaged genes. Cells with damaged genes often die out. But, some may grow into a tumor. In the case of 22q13 deletion syndrome, cancer is extremely rare. However, there can be other problems when a gene is a pathogenic variant, or when a chromosomal deletion removes only part of a gene. A partially deleted gene can start creating proteins that interfere with normal cell operation (see When missing a gene is a good thing.) So, a bigger deletion could be actually be less pathogenic than a slightly smaller deletion if the smaller deletion disrupts just part of a gene. It is probably not very common, but a partial deletion or unfortunate pathogenic variant could cause of more severe problems.
4. Gene combinations. Most geneticists evaluate a deletion based on the impact of individual genes. But, current scientific studies suggest a lot more complicated things can happen when multiple genes are involved. Research in autism spectrum disorder, schizophrenia and other disorders show that these disorders are often caused when a large number of common gene variants combine together in an unfortunate way. Each variant 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 subtle and still poorly understood. Older research used the term “genetic background” to act as placeholder. More recent work has led to a newer concept called “polygenic risk”. The main genetic differences between my cousin’s daughter and my son are from our spouses, who each contributed different background genetics. Somehow, the genes from my spouse collectively lead to life-threatening problems as a newborn when mixed with his 22q13 deletion. My cousin’s daughter received a less threating set of background genes from her father.
5. Mosaicism and somatic mutations. Recent evidence shows that it is possible for a genetic error to occur in one small region of the brain. That is, some 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 if they occur in the region of 22q13. In cases of pathogenic SHANK3 variants, the impact of SHANK3 may be greatly amplified by errors in other genes in specific brain regions. Blood tests often do not show mosaic/somatic errors that may occur deep in the brain.
6. Genetic regulators (elements). Since 2009 the ENCODE genetics project (https://www.encodeproject.org/) and others have sought to find the bits and pieces of DNA that regulate genes. Genes make up the minority of DNA. Most of DNA is comprised 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 genes necessary for the skin. Brain cells only use genes necessary for brain. The DNA is regulated in each tissue to match the needs of that tissue. Chromosome 22 deletions not only knock out genes, they knock out genetic regulators. A 4.7 Mb terminal deletion may not hit any more genes than a 4.8 Mb deletion, but it may hit a crucial regulator site. Gene regulators are not impossible to detect, but they can be difficult to study. Whole exome sequencing, a powerful tool for finding small genetic errors, skips over most of the gene regulators. Gene regulators are a likely cause of many unexplained differences.
7. Healing. DNA can be a very sticky substance. When a terminal deletion occurs (the most commonly observed occurrence in 22q13 deletion syndrome), the broken end of the chromosome can pick up various bits and pieces of DNA as it “heals” (re-seals the ends). In the extreme case the chromosome forms a ring by attaching to its opposite end. In other cases the end of the chromosome may pick up bits and pieces of DNA, sometimes copies of itself. The random junk at the end of a deletion could have an important impact, although this has not been carefully studied.
8. Positional effects. Positional effects is related to genetic regulators. The location of a gene relative to other genes and regulators on the same chromosome can be important. Enhancers, for example, are regulator elements that increase the likelihood that a gene will get used to produce its product (usually a protein). The distance between a gene and its enhancer may strongly influence how effectively the enhancer operates. Deletions, especially interstitial deletions, can change the distance between DNA elements and ultimately influence the impact of a deletion. Positional effects help explain why two similar size deletions might have noticeably different outcomes.

Final thoughts

Given the complexity and many opportunities for unexplained variation, we can begin to appreciate why knowing an individual’s deletion size does not provide all the answers. But, even with the wide person-to-person variation, studies have shown that larger deletions have a more serious impact than smaller ones. Some of my other blogs discuss specific genes and even ways to explore the influence of genes of unknown function. Parents should appreciate that it takes time to incorporate new science into medical practice. Genetic reports in the future will likely say a lot more about specific genes than reports today. If your genetic report provides a list of genes lost in a deletion, hold onto that list. Genes of “unknown significance” may someday be identified as important.

arm22q13

Some previous posts:

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.
I
Understanding deletion size
22q13 deletion syndrome – an introduction