Congenital disorder of glycosylation, type ia

Diagnosis and Testing

What is the most likely result for congenital disorder of glycosylation type 1A genetic testing?

If your child is having genetic testing done due to a biochemical or enzymatic diagnosis of congenital disorder of glycosylation type 1A (CDG-Ia), it is likely that the genetic testing will find a mutation. Enzymatic diagnosis means that your doctor has ordered testing to look at the enzyme made by the PMM2 gene, phosphomannomutase. If the enzyme is not working like expected, mutations would likely be found in the gene. In these cases where there is low enzyme activity, very close to 100% of individuals will have identifiable mutations. Speak to your doctor or genetic counselor if you have questions about the likelihood that genetic testing will find a mutation in the PMM2 gene.

References
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My child was found to have a mutation and a variant of uncertain significance in the PMM2 gene. Will they do more testing?

How does the laboratory know whether something is a VUS, likely pathogenic, likely benign, positive, or negative result in relation to congenital disorder of glycosylation type 1A?

How do I get tested for congenital disorder of glycosylation type 1A?

Is there newborn testing for congenital disorder of glycosylation type 1A?

Are there different types of tests for congenital disorder of glycosylation type 1A?

Is it recommended to test children for congenital disorder of glycosylation type 1A?

Does it matter if you test blood vs. saliva vs. biopsy for congenital disorder of glycosylation type 1A?

What does it mean to have a "variant" in the gene for congenital disorder of glycosylation type 1A?

Where can I go to learn more about variants of uncertain significance in congenital disorder of glycosylation type 1A?

How does my child get "worked-up" for congenital disorder of glycosylation type 1A?

Is there a common mutation that most people with congenital disorder of glycosylation type 1A have?

My ethnicity is of European descent. What are the chances I could be a carrier of congenital disorder of glycosylation type 1A?

I have heard that you can have genetic testing done for congenital disorder of glycosylation type 1A through a "carrier-screening panel". What exactly does that mean?

What laboratories offer screening for congenital disorders of glycosylation type 1A?

I had negative carrier screening test for congenital disorder of glycosylation type 1A. Does that mean I am no longer at risk?

If I wanted to do further testing for congenital disorder of glycosylation type 1A after common mutations on carrier screening, what would it be?

My partner was found to be a carrier of a mutation in the PMM2 gene. What are my next steps?

My child was found to have a mutation and a variant of uncertain significance in the PMM2 gene. Will they do more testing?

If your child underwent testing for congenital disorder of glycosylation type 1A (CDG-Ia) and was found to have a variant of uncertain significance (VUS) in the PMM2 gene, it is possible that the doctor and genetic counselor will want to do more testing. This is done to try and get as much information as possible in order to have a better idea of whether the VUS is a mutation or benign change. In order for a child to have this condition, they must have two mutations in the PMM2 gene. If one known mutation and one VUS is found, it is suspicious that the VUS is a mutation. However, we cannot say for sure. The next steps are highly dependent on your family history and the results from the genetic testing. The genetic counselor will be able to explain what the next steps are if a VUS is found. Other possible testing might include analysis of biochemical testing or enzymatic testing.

References
How does the laboratory know whether something is a VUS, likely pathogenic, likely benign, positive, or negative result in relation to congenital disorder of glycosylation type 1A?

Laboratories follow the guidelines made by the American College of Medical Genetics and Genomics (ACMG). These guidelines tell the labs what evidence and information they need in order to classify variants in each of those categories. These updated recommendations were just recently made in March 2015, so it is possible that websites or other research may use the old terms. If you have questions about variant classification, speak with your genetic counselor or the doctor who ordered your genetic testing.

References
  • Genetics Home Reference. https://ghr.nlm.nih.gov/primer/testing/interpretingresults
  • Interpreting the Results of a Genetic Test. http://www.nchpeg.org/index.php?option=com_content&view=article&id=172&Itemid=64
How do I get tested for congenital disorder of glycosylation type 1A?

Testing for congenital disorder of glycosylation type 1A can be ordered by your doctor or genetic counselor. There is genetic testing and biochemical testing that can be performed. There are many laboratories that offer genetic testing for the condition. It involves either a blood or saliva sample. Results take about 4-12 weeks depending on the laboratory.

The best person to figure out whether an individual has CDG-Ia is a doctor who specializes in metabolic disorders, such as a biochemical geneticist. A biochemical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website .

Is there newborn testing for congenital disorder of glycosylation type 1A?

Congenital disorder of glycosylation type 1A is not a condition that is tested for on the newborn screen. However, if it is suspected at birth, testing infants is reasonable. Many laboratories offer testing for congenital disorder of glycosylation type 1A. Speak to your doctor or genetic counselor to learn more about your options for biochemical and genetic testing.

References
Are there different types of tests for congenital disorder of glycosylation type 1A?

There are a few testing options available for congenital disorder of glycosylation type 1A (CDG-Ia).

  • Carbohydrate deficient transferrin (CDT) analysis is a test which examines how a protein in the blood is glycosylated. This is a "screening" test, meaning that if it is abnormal, additional testing must be done to confirm a diagnosis. Based on the CDT results, a doctor may be suspicious that a person has CDG-Ia.
  • N- and O-linked glycan analysis is another biochemical screening test. In this test, the specific sugar molecules are analyzed on many different proteins. This test can differentiate between different types of congenital disorders of glycosylation, but additional testing is required to confirm a diagnosis of a specific CDG.
  • Genetic testing for mutations in the PMM2 gene can be performed. If two mutations are found in the PMM2 gene, it confirms a diagnosis of CDG-Ia in that person.
  • Genetic testing can also be performed for multiple genes at one time. These are called "panels". PMM2 is often included on panels of genes for congenital disorders of glycosylation.
  • Mutations in PMM2 could be identified on whole exome sequencing. Whole exome sequencing is a genetic test in which all expressed portions of genes are analyzed.

The best person to figure out whether an individual has CDG-Ia is a doctor who specializes in metabolic disorders, such as a biochemical geneticist. A biochemical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website .

References
Is it recommended to test children for congenital disorder of glycosylation type 1A?

Since symptoms occur at birth and during childhood, it is reasonable to test children for congenital disorder of glycosylation type 1A (CDG-Ia) if it is suspected. If the child has no symptoms, it is possible that the condition could develop later on in life due to the variation in ages of onset. However, it is not a routine test to test asymptomatic children for CDG-Ia.

The best person to figure out whether an individual has CDG-Ia is a doctor who specializes in metabolic disorders, such as a biochemical geneticist. A biochemical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website .

References
Does it matter if you test blood vs. saliva vs. biopsy for congenital disorder of glycosylation type 1A?

Different sample types are used for different types of testing for congenital disorder of glycosylation type 1A (CDG-Ia). Genetic testing may be performed on either blood or saliva. There are no differences in the accuracy of the genetic testing if blood or saliva is used. Many laboratories offer both blood or saliva for testing. The testing is completed in the same way for both blood and saliva. Biopsies are typically not needed for the diagnosis of CDG-Ia. Speak with your doctor about what types of tests are being performed and what samples are needed for the testing.

References
What does it mean to have a "variant" in the gene for congenital disorder of glycosylation type 1A?

A "variant" is another name for change in a gene. Pathogenic variants are changes in the gene that are known to cause disease and are also called mutations. Benign variants are changes in the gene that do not cause disease. Changes can often be called "variants" if they are classified as variants of uncertain significance (VUS). If you have testing done for congenital disorder of glycosylation type 1A and are found to have a "variant" in the PMM2 gene, it means that it is not exactly known if it is a mutation or a benign change. Further testing of family members may be necessary in order to know for sure whether the variant is the cause of the symptoms. You should talk to your doctor or genetic counselor to learn more about the particular variant found in your family.

References
Where can I go to learn more about variants of uncertain significance in congenital disorder of glycosylation type 1A?

You can learn more about variants of uncertain significance through the various laboratories that offer genetic testing. Many laboratories explain their processes for interpreting variants found in their tests. There is a very strict criteria developed by the American College of Medical Genetics (ACMG). This criteria attempts to ensure that each laboratory is interpreting these variants in the same way. A genetic counselor can help you retrieve this information. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

References
How does my child get "worked-up" for congenital disorder of glycosylation type 1A?

Congenital disorder of glycosylation type 1A may be suspected based on clinical features. The diagnosis is confirmed by biochemical or genetic testing. Geneticists and genetic counselors will likely do a full evaluation, which will include a discussion of birth history, medical history, and developmental history. The geneticist will perform a physical exam. This is done because there may be additional recommendations or specialists they will refer you to for the best care possible. Speak with your child's pediatrician if you are concerned that he or she may have CDG-Ia. The best person to figure out whether an individual has CDG-Ia is a doctor who specializes in metabolic disorders, such as a biochemical geneticist. Biochemical geneticists can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website .

References
Is there a common mutation that most people with congenital disorder of glycosylation type 1A have?

There are 4 common mutations in the [I]PMM2[/I] gene that are found in people with congenital disorder of glycosylation type 1A (CDG-Ia). The first is called the p.Arg141His mutation. This mutation is mostly found in the compound heterozygous state, meaning that a person with congenital disorder of glycosylation type 1A has one copy of the p.Arg141His mutation and another mutation. The p.Arg141His mutation is found in 40% of individuals with congenital disorder of glycosylation type 1A. There are also three mutations found in individuals of European ancestry that are commonly found. The first is the p.Phe119Leu mutation. This is found in people from northern Europe. Two other variants are p.Val231Met and p.Pro113Leu. These variants are found in patients with European ancestry.

In order to learn more about the gene involved in CDG-Ia, people can speak with a geneticist or a genetic counselor. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

References
My ethnicity is of European descent. What are the chances I could be a carrier of congenital disorder of glycosylation type 1A?

There is about a 1 in 71 chance (1.4%) that someone of European ethnicity could be a carrier of congenital disorder of glycosylation type 1A (CDG-Ia).

In order to learn more about the gene involved in CDG-Ia, people can speak with a medical geneticist or a genetic counselor. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

I have heard that you can have genetic testing done for congenital disorder of glycosylation type 1A through a "carrier-screening panel". What exactly does that mean?

A carrier-screening panel is a genetic test used to identify people who are carriers for mutations associated with different genetic disorders. Many of these conditions are autosomal recessive disorders. The genetic conditions recommended for screening before and during pregnancy can be dependent on your ethnic background. There are many carrier-screening tests available. It is possible to test for just a few syndromes, or hundreds of syndromes at the same time. If a carrier screening includes congenital disorder of glycosylation type 1A, it may only include the three most common mutations in European individuals. Not all carrier-screening panels include this condition. Additionally, some labs require that you specifically request screening for this condition. If you are interested in having this testing done, talk with your doctor or genetic counselor to learn more. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

What laboratories offer screening for congenital disorders of glycosylation type 1A?

To learn more about what labs offer screening and testing for congenital disorders of glycosylation type 1A, you can visit GTR: Genetic Testing registry (http://www.ncbi.nlm.nih.gov/gtr/). To learn more about screening options, you can speak with a geneticist or a genetic counselor. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

I had negative carrier screening test for congenital disorder of glycosylation type 1A. Does that mean I am no longer at risk?

Screening tests are not perfect. Some carrier screening tests for congenital disorder of glycosylation type 1A (CDG-Ia) only test for the most common mutations in individuals of European ethnicity. That means there is still a risk that you carry a mutation that was not tested, particularly if you are not of European ethnicity. If you have a family history of congenital disorder of glycosylation type 1A, or if there is any reason you suspect you may be a carrier, you should speak to your doctor or genetic counselor about further testing. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

References
If I wanted to do further testing for congenital disorder of glycosylation type 1A after common mutations on carrier screening, what would it be?

If there is a family history or another suspicion for congenital disorder of glycosylation type 1A, your doctor or genetic counselor may recommend having full gene sequencing of the PMM2 gene. This means that instead of looking for specific mutations, they are looking at the entire instruction to see if there are any changes. These changes would be the mutations that cause the condition. This testing can tell you whether you have any mutations in the gene, not just the most common 3 mutations. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

References
  • LabCorp. Congenital disorder of glycosylation type 1A. https://www.labcorp.com/wps/wcm/connect/IntGeneticsLib/integratedgenetics/resources/diseases/congenital+disorder+of+glycosylation,+type+1a?Congenital%20Disorder%20of%20Glycosylation%20Type%201a
  • PMM2-CDG (CDG-Ia). Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1110/
My partner was found to be a carrier of a mutation in the PMM2 gene. What are my next steps?

If your partner is known to be a carrier of a mutation in the PMM2 gene, you should talk to your doctor or genetic counselor about the next steps. Most likely they will recommend full gene sequencing for you to look for any mutations in the entire instruction in the PMM2 gene. This testing is >99% accurate at determining whether you are a carrier of a mutation in the PMM2 gene. This testing is necessary to better determine your and your partner's risk of having a child with congenital disorder of glycosylation type 1A.

References
  • LabCorp. Congenital disorder of glycosylation type 1A. https://www.labcorp.com/wps/wcm/connect/IntGeneticsLib/integratedgenetics/resources/diseases/congenital+disorder+of+glycosylation,+type+1a?Congenital%20Disorder%20of%20Glycosylation%20Type%201a
  • Genetic Carrier Screening. Johns Hopkins University. http://www.hopkinsmedicine.org/fertility/resources/genetic_screening.html

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