Genetic Testing

Cohen Syndrome Inheritance and Testing Options

Cohen syndrome is an inherited disorder caused by changes in the VPS13B gene. Affected individuals will have a change in the copy of the gene inherited from mom as well as a change in the copy of the gene inherited from dad. Inheritance of a gene change from each parent resulting in disease is called autosomal recessive. Individuals with just one gene change in an autosomal recessive disorder will usually not have any clue that they are a carrier of the gene change; no health problems, no mild symptoms of the disease, and for many families, no history of the disease. If the parents have relatives in common and a family history of an autosomal recessive disease, then the risk that they are each carriers of the disease is increased. Once a child is diagnosed with an autosomal recessive disorder, then the parents have a 1 in 4 chance with each pregnancy of having another affected child. The unaffected siblings of an affected child each have a 2 in 3 chance to be a carrier of the disease-causing gene.
Carrier testing of family members is not recommended without genetic or molecular confirmation of the gene changes in the affected individual. Without confirmation of the affected individual’s gene change(s) there is always the possibility that carrier testing is being performed on the wrong gene. With Cohen syndrome as well as many other genetic disorders, there are some individuals who are misdiagnosed, for many different reasons. Carrier testing of the sibling of a “misdiagnosed” Cohen syndrome patient would tell us that this person is not a carrier of Cohen syndrome but this unaffected individual may in fact be a carrier of the same disorder as the affected sibling.
Genetic testing to confirm the diagnosis of Cohen syndrome is available. There are two methods of testing that may be required. Gene sequencing will pick up small changes in the VPS13B gene but will miss large changes such as a large deletion or duplication. Targeted microarray analysis of the VPS13B gene is used to detect these large deletions and duplications. Many affected individuals will have a small change on one gene and then a larger change on the other gene, meaning that both sequencing and targeted microarray may be necessary for genetic confirmation of Cohen syndrome.
Once the genetic changes in the Cohen syndrome patient are known, carrier testing can be offered to family members including siblings. Even though parents will already know that they are each carriers of a Cohen syndrome gene change, they may wish to have carrier testing for several different reasons. These reasons for carrier testing include future family planning and sharing of the gene change information with extended family members such as aunts, uncles and cousins of the affected individual. Knowledge of the specific gene changes allows carrier testing by means of known familial mutation (KFM) analysis. This means that the carrier testing should be much cheaper than the price of the testing for confirmation on the affected individual. There are also several ways to perform the testing sequentially to try to reduce costs further. For instance, if the affected individual has both a gene sequence change and a large deletion detected by targeted microarray, one parent could start with KFM analysis for the gene sequence change. If the change is detected, then the other parent would need only targeted array for the large deletion. If the sequence change is not detected in the first parent, targeted array should be performed to confirm the presence of the large deletion. Then the second parent can move forward with the sequence analysis. Once this parental carrier testing is completed, extended family members can use a copy of the carrier testing results to arrange for the appropriate KFM testing.
Just to confuse the carrier testing issue further, it is possible that one parent will test positive for a Cohen syndrome gene change and the other will not. This occurs more often than one would think and may be due to mosaicism. Mosaicism means that there is a mix of cells and gene changes in those cells. Mosaicism can be germline (affecting only egg or sperm cells), somatic (affecting cells other than egg or sperm cells), or a combination of both. For a parent who tests negative as a carrier and paternity is not in question, the parent is likely to be a carrier in at least some or all of either the egg or sperm cells. Genetic testing may or may not be able to detect a genetic variation in a mosaic individual, depending on how many cells and which cells harbor the genetic variation. Egg and sperm cells are not tested for carrier status, so confirmation of the result may depend on carrier testing of unaffected children, siblings or extended family members. Confirmation may not be possible for many families, due to small family size or the mosaic carrier change being new (de novo), such that there is no other carrier in the family of this parent. Having one parent with unconfirmed carrier status should not change the option for future prenatal or newborn testing as long as the genetic test results for the affected child are available.
There are at least 16 laboratories worldwide offering whole gene sequencing of the VPS13B gene, many of whom will also offer deletion/duplication analysis. Laboratories that offer whole gene sequencing will usually also offer KFM testing for the carrier testing. This list of laboratories includes the Molecular Diagnostics Laboratory at the DDC Clinic ~ Center for Special Needs Children.

Article submitted by Christine Wensel, MS, LCGC, genetic counselor at DDC Clinic. DDC Clinic ~ Center for Special Needs Children has a long history of caring for children who have Cohen syndrome. Dr. Heng Wang is involved in the care of at least 70 patients, Amish and non-Amish, diagnosed through DDC clinic.