Pompe disease

Inheritance

How is Pompe disease inherited?

Pompe disease is caused by a change (also called a mutation or a variant) in the GAA gene which causes the gene to not work correctly. The GAA gene carries the instructions for making the alpha-glucosidase enzyme, also called acid maltase, which is important for breaking down glycogen in the body. We normally have two working copies of GAA in our cells and we inherit one copy from our biological mother and the other from our biological father. In order to develop symptoms of Pompe disease, both copies of GAA are not working properly. This is also called autosomal recessive inheritance, which means that both parents of someone with Pompe disease are carriers of one working and one non-working copy of the GAA gene. Since each parent has one working copy, they don't have symptoms of Pompe disease themselves. However, when they have children, they each have a 1 in 2 or 50% chance of passing on the non-working copy to their child. When both parents are carriers, there is a 1 in 4 or 25% chance of both of them passing on the non-working copy and having a child with Pompe disease. Even if a couple already has one child with Pompe disease, it is important to know that they can have another affected child because the chances are 1 in 4 for each pregnancy.

References
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What does it mean to have inherited a mutation or change in the gene for Pompe disease?

What does it mean to have inherited a variant in the gene for a disease?

Are there forms of Pompe disease that aren't genetic?

What does it mean to have inherited a mutation or change in the gene for Pompe disease?

People have around 20,000 genes in every cell of our bodies. Almost all of our genes come in pairs. We get one copy of each gene from our mother in the egg cell and the other copy from our father in the sperm cell. Pompe disease is caused by having two non-working copies of the GAA gene. When a person has a non-working copy of a gene, it is due to a change in that gene and may also be called a mutation. A person with one working GAA gene and a mutation in their other gene are called carriers. Carriers do not have any symptoms of Pompe disease because they still have one working copy of the gene. They usually inherited the mutation from either their mother or their father, and they can pass on either the mutation or the working copy to each of their children. There is a 50% chance of passing on the mutation or non-working gene to each child.

References
What does it mean to have inherited a variant in the gene for a disease?

Sometimes, after having a genetic test, the lab finds a change that is classified as a variant of uncertain significance (VUS). A VUS is a change in the genetic instructions that the medical community does not know yet if it causes health problems or not. That is because there are some differences in the genetic code that are different from person to person, but do not cause health problems.

When a new change or variant in a gene or chromosome is found, the lab first tries to figure out if it would be expected to cause health problems. First, they determine if change has been seen in other people with the disease. If it is present in people with the disease and not in people without the disease, it is more likely to be a disease-causing change. Second, they look to see if the variant is in a place where the code is the same in other animals that make the protein (conserved across species) or is different in other animals (non-conserved across species). In conserved areas of the gene, it is more likely to be an important part of the code to make the protein work right. Lastly, the lab looks at what the change may do to the enzyme or protein being made by that gene. If the change causes the code of the gene to stop reading (called a premature stop codon), it is likely to be a disease causing change because the whole protein can't be made. If the change causes the gene to code for a different building block of the protein (amino acid substitution or missense change), it can be either a disease-causing change (pathogenic) or cause no problems (benign). If the change is in a non-coding part of the gene, it is slightly less likely to cause problems. There are computer programs that help the lab determine if a change is more or less likely to cause problems, called Polyphen and SIFT. Ultimately, if the lab doesn't have enough information to decide whether the change causes a problem to the gene or not, they call it a variant of uncertain significance or VUS.

When more information becomes available about that specific change or variant, it may be reclassified as pathogenic (disease-causing), likely pathogenic (likely disease-causing), likely benign (likely not disease causing), or benign (not disease causing). However, reclassification can take a long time and not all laboratories doing testing watch for new data available to change a VUS's classification and/or issue new reports. For some perspective, more than 80 million genetic variants have been uncovered in the human genome, and for the most there is no clear understanding of their role in human health and disease. The best way to know if a VUS has been reclassified as disease causing or not is for the person with the test result to ask their doctor to double check with the laboratory. The doctor should ask the laboratory for a updated review of current information on the change and if the VUS will be or has been reclassified. For some genes such as BRCA1 and BRCA2, websites have been created by laboratories that make it very easy for a doctor to find out if a VUS has been reclassified. Examples include: BRCA Share for BRCA1 mutations by Quest diagnostics.

In addition to talking to a genetics focused health care professional, there is also a project at the University of Washington that works with people with a VUS to speed up that process by working with their family members directly. To learn more about the project and review helpful resources, visit the Find my Variant project website.

For people found to have a VUS in a hereditary cancer gene via a multiplex gene panel test that looks at many different genes, there is a registry study called Prospective Registry of Multiplex Testing (PROMPT) that is designed for patient participation. The goal is to help doctors and patients learn more about the genes tested on the panel and report any useful information directly back to the person with the VUS.

For individuals with a VUS in BRCA1 or BRCA2, they may also choose to participate in the the "Free the Data" project. "Free the Data" is a grassroots initiative which asks people who have had genetic testing for the BRCA1 and BRCA2 genes to share their results and health information with the "Free the Data" team so that they can enter them into ClinVar, an open-access database of mutations run by the NIH in order to gain a better understanding of hereditary breast and ovarian cancer. This step is important as not all testing laboratories enter their information into confidential, but publicly accessible databases like Clinvar where researchers can use them. The goal of the "Free the Data" movement is to understand more information about mutations and variants of unknown significance (VUS) in BRCA1 and BRCA2. Over time, the campaign hopes to expand to encompass all genes and all mutations, powering new research and better health for all. To learn more about the "Free the Data" movement and how people can be involve visit the Free the Data website.

References
  • Genetics Home Reference
  • National Coalition for Health Professional Education in Genetic (NCHPEG) http://www.nchpeg.org/microarray/what-do-other-results-mean
  • "ClinGen- The Clinical Genome Resource" N Engl J Med 2015; 372:2235-2242June 4, 2015http://www.nejm.org/doi/full/10.1056/NEJMsr1406261
Are there forms of Pompe disease that aren't genetic?

As far as the medical community knows now, all forms of Pompe disease are caused by changes in the GAA gene. There are no other genetic causes or things in the environment that cause Pompe disease.

References

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