What important genes (genetic instructions) on chromosome 22q13.3 can lead to medical concerns seen in Phelan-McDermid syndrome?
The three genes in the "critical" region for Phelan-McDermid syndrome include SHANK3, ACR, and RABL2B. The SHANK3 gene is completely or partially deleted (missing) in almost all cases of Phelan-McDermid syndrome. Having a missing (deleted) copy of SHANK3 is linked to speech problems and intellectual disability. In some rare cases of Phelan-McDermid syndrome a chromosome rearrangement or mutation (change) disrupts the SHANK3 gene. The other genes in the critical region most likely also play a part in some of the additional features that can be seen in Phelan-McDermid syndrome. More research is needed to find out exactly how the deletion of these genes causes the features seen in Phelan-McDermid syndrome. If you have a child with absent or delayed speech, developmental delay or any other features that can be seen in Phelan-McDermid syndrome, talk to your doctor about getting testing for this syndrome.
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How common is Phelan-McDermid syndrome?
At least 500 cases of Phelan-McDermid syndrome are known. Based on limited information, it is predicted that about 2.5-10 per million births have Phelan-McDermid syndrome. This is likely an underestimate as Phelan-McDermid syndrome remains undiagnosed in many people. If you have a family member with the symptoms of Phelan-McDermid syndrome, talk to your doctor about testing.
How is Phelan-McDermid syndrome inherited?
Most cases on Phelan-McDermid syndrome are not inherited. In these cases, there is no family history and the chromosome 22q13.3 deletion occurs randomly during the formation of the sperm cells or egg cells, or in early development. These are called "de novo" cases. There is nothing that a parent does to cause a "de novo" deletion on chromosome 22 in their child. This event occurs randomly. About 20% of the time, deletions of chromosome 22q13.3 are caused by an unbalanced chromosome rearrangement. In these cases a parent may have a balanced chromosome rearrangement that can lead to a chromosome 22q13.3 deletion in their child. When a parent has a balanced chromosome rearrangement, they have all of their chromosomal material but it is just rearranged. The parent is not typically affected because all of their chromosomal material is present. However, when they have children, a parent is at an increased risk to have a child with an unbalanced amount of chromosomal material [too much (duplication) and/or too little (deletion)]. Sometimes, an unbalanced chromosome rearrangement occurs brand new (de novo) in the child and causes a chromosome 22q13.3 deletion. In rare cases, Phelan-McDermid syndrome is caused by a chromosome rearrangement that disrupts the SHANK3 gene or a change (mutation) in the SHANK3 gene. If you have a child with Phelan-McDermid syndrome, talk to your doctor or a genetic counselor to find out which or these causes is the reason for Phelan-McDermid syndrome in your child.
Are all chromosome 22q13.3 deletions the same?
Not all chromosome 22q13.3 deletions are the same. Some chromosome 22q13.3 deletions are larger while others are smaller. Typically, the larger the deletion, the more severe the symptoms will be. However, it can be difficult to predict the exact symptoms a person with Phelan-McDermid syndrome will have based on the size of the deletion. Sometimes, a child can have another chromosome difference in addition to a chromosome 22q13.3 deletion. This will often cause the individual to have additional symptoms. Speaking to a genetic counselor or a medical geneticist can help you find out what type of deletion a person with Phelan-McDermid syndrome has.