Over the years, there has been a lot of confusion about the deletion that is the cause of Jacobsen syndrome (JS).  Most children with Jacobsen syndrome have a “terminal” deletion in the long (“q") arm of chromosome 11, meaning the deletion extends to the end of the chromosome.  That is the most common deletion that causes JS. Alternatively, there can be so-called “interstitial” deletions that occur within the region that is typically affected in patients with a terminal deletion, but does not extend to the end of the chromosome.  Depending on what part of the chromosome is affected, people with an interstitial deletion can have many of the same problems as those with a terminal deletion.

 

One major source of confusion has been the nomenclature used to describe a deletion.  This stems from which genetic test was used to identify the deletion. The original cases were based on the results of a karyotype analysis, in which specific bands (e.g., 11q23.3) can be identified using special staining techniques that can be seen under a microscope.  Although this test gives a qualitative description as to whether there is a deletion, its resolution is limited (see below) and does not give any specific information regarding affected genes. Furthermore, patients with different size deletions (and different clinical features) can still be described as having the same deletion based on the karyotype analysis (e.g., a deletion in 11q23.3).  Karyotype analysis has very limited resolution and cannot detect deletions smaller than about 5Mb.

 

More recently, a much more sophisticated test has been developed that describes the deletion breakpoint location and size at the molecular level.  As background, chromosome 11 is about 135 million base pairs (megabases, Mb) long and contains several hundred genes. Terminal deletions in the long (q) arm of chromosome 11 can range up to about 16 megabases.  Terminal deletions larger than that are probably not compatible with life. This test, called “array comparative genomic hybridization” (aCGH), or sometimes “microarray”, defines the breakpoint location to the exact base pair.  Typically, the deletions are reported to the nearest tenth of a megabase (e.g., 10.3Mb). Because this technology can pinpoint the location of the deletion, a readout of all of the affected genes can then be easily generated. This information can then be used to help predict some clinical outcomes, although that can be quite complicated.  As an example, we know that every child that has a terminal deletion larger than 12Mb has significant intellectual disability. That’s because we know there is a gene (BSX1) located 12Mb up from the end of the chromosome that is essential for cognitive function. This information can be extremely important to “stratify” people to determine if they might respond to our “gene-specific” therapies, i.e., medications that we think could help to restore the function of a specific deleted gene.  Unfortunately, this information isn’t always helpful. For example, we now know that even some people with smaller deletions not involving BSX1 can also have significant intellectual disability, although we don’t know why. Clearly there are multiple factors that can contribute to the clinical problems. Another example is the gene that causes heart defects, ETS1. We definitely know that loss of the ETS1 gene is the cause of heart defects, but we don’t know why only about half of all people with JS that are missing a copy of the ETS1 gene have a normal heart. 

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Categorizing deletions as small, medium or large is somewhat arbitrary.  I consider a deletion larger than 12Mb to be large, about 10-12Mb medium, and less than 10Mb to be small.  It should also be noted that although there are dozens of genes that are lost by the deletion, it is estimated that only about 10% of these genes have any clinical significance.  In other words, for many of the genes that are deleted, there is no effect. Of note, aCGH can detect tiny deletions (less than 1Mb) that cannot be detected by a karyotype analysis.

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Is there a genetic test that can determine if either parent has an abnormal chromosomal finding?

• Yes, a karyotype analysis can be ordered by a geneticist to determine if the parent is either a carrier of a balanced translocation or may themselves have a deletion (but smaller deletions will not be detected by a karyotype analysis). 

 

What are the odds of having another child with Jacobsen syndrome in the same immediate family if neither parent has an 11-chromosome anomaly? 

• I know of a few cases in which this has happened. Overall, I estimate that the chance of recurrence in which the parents have a normal karyotype is about 1%. 

 

What are the odds of having another child with Jacobsen syndrome if one parent has an 11-chormosome anomaly?

• This becomes complex and is variable, but if a parent has a balanced translocation then the odds are very high that they can have an affected child or a child that is a carrier who would then have a high risk of having an affected child. The siblings of an affected parent should also be tested to determine if they might be affected too. A geneticist can help by ordering the necessary tests and explaining the results. 

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What are the odds of a Jacobsen syndrome individual’s sibling having a child with Jacobsen syndrome?

• If the sibling has a normal karyotype (and aCGH), then the odds are probably not any higher than for the general population, which is roughly 1 in to 50,000 to 1 in 100,000. I am not aware of any case in which an unaffected sibling has had a child with JS. 

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What are the odds of giving birth to a child with Jacobsen syndrome if either the mother or father has Jacobsen syndrome?

• 50%

 

For additional information and details on genetics, please watch the video from the 2014 11q conference by Dr. Marie Del’Aquilla: Introduction to Chromosomes and Genetic Technologies