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In this study of 56 individuals, Heather Wilson and colleagues examined the size of the 22q13 deletion and the parental origin of the deletion. They also studied the gene SHANK3 (also called ProSAP2) to help understand its role in Phelan-McDermid Syndrome. Many of the families participating in this study are members of our Support Group.
When the end of a chromosome is lost or deleted, the loss may occur on the chromosome inherited from the father or the chromosome inherited from the mother. In many chromosome deletion syndromes, including deletions of the long arm of chromosome 18 (18p- Syndrome) and deletions of the short arm of chromosome 4 (Wolf-Hirschhorn Syndrome), the loss occurs more frequently on the chromosome inherited from the father than from the mother. The increased number of deletions on the father's chromosome seems to indicate a greater chance of deletions occurring in sperm than in eggs. Among the individuals with Phelan-McDermid Syndrome, about two-thirds had deletions on chromosome 22 inherited from their father while about one-third had deletions on chromosome 22 inherited from their mother. This finding is not surprising since similar results have been seen in other terminal deletion.
The size of the deletion on chromosome 22 can be very small (only 130 kilobases) or very large (9 megabases). A kilobase (kb) is 1,000 bases while a megabase (Mb) is 1 million bases. Bases are the units that make up our DNA and they are called adenine (A), thymine (T), guanine (G) and cytosine (C). We have 6 billion to 7 billion base pairs of genetic material that is arranged into our 46 chromosomes. A deletion that is 3 Mb or larger usually can be seen by G-banded chromosome analysis. Deletions less than that require FISH studies or DNA studies for detection.
The size of the deletion on chromosome 22 does not correlate with the physical features of Phelan-McDermid Syndrome. Individuals who are missing smaller pieces of the chromosome have similar features to individuals who are missing larger pieces of the chromosome. Likewise, all individuals have some degree of developmental delay and speech delay, regardless of the size of the deletion.
The gene SHANK3 is near the end of chromosome 22. The gene codes for a structural protein that is important in the formation of synapses or connections between the nerve cells. These synapses allow impulses to travel from one nerve cell to another. In this study, all of the individuals with deletion 22q13 were missing one copy of the SHANK3 gene. This means that less of the protein is available for forming synapses (or more precisely, the post-synaptic structures) and that the synapses may be less efficient than those formed with the normal amount of SHANK3. Loss of one copy of SHANK3 is thought to be responsible for the neurological problems (developmental delay and absent speech) in deletion 22q13.
As we know, some individuals with Phelan-McDermid Syndrome may acquire a certain skill, such as speaking a few words, and later lose that skill. The skill may be regained at a later time. The loss of a learned skill could also be related to the deficiency of SHANK3. Synapses formed with a reduced amount of SHANK3 may be more inefficient than those formed with the correct amount of SHANK3. As new skills develop and more extensive synapses form, the risk of failure of the neural network increases. Eventually, as the neural network fails, the individual may experience a loss of a particular skill.
This study supports the role of SHANK3 in contributing to the neurological symptoms of the 22q13 Deletion Syndrome.
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