We expect many more people will get a diagnosis of Smith-Kingsmore syndrome as awareness of the condition increases. SKS is a rare condition that many physicians are not familiar with. A diagnosis of SKS is suspected based upon the identification of characteristic features, a detailed patient and family history and a thorough clinical evaluation.
A diagnosis of SKS is confirmed with the detection of a germline or mosaic mutation in the MTOR gene. A genetic test performed on a sample of blood or saliva will detect a mutation that is present in all cells of the body (germline variants). To detect a mutation only present in some cells (somatic mosaicism), the genetic test must be performed on a sample of affected tissue.
Some individuals with SKS may be diagnosed with a molecular genetic test that covers a subset of genes related to the individual’s symptoms (gene panel testing). Others may have whole exome sequencing (WES) or whole genome sequencing (WGS). These methods rely on new technologies that allow rapid sequencing of large amounts of genetic material. This is known as next-generation sequencing (NGS).
The appropriate testing should be discussed with the care team.
Whole Exome Sequencing
Using NGS researchers can now sequence all pieces of an individual’s DNA that provide instructions for making proteins. These pieces, called exons, are thought to make up 1 percent of a person’s genome. All the exons in a genome are known as the exome. The method of sequencing them is known as whole exome sequencing. WES identifies variations in the protein-coding region of any gene, rather than in only a select few genes.
WES detects genetic spelling errors, called variants, in genetic sequence. Some variants are benign, meaning they do not cause disease. Next, some variants, called variants of unknown significance, have uncertain effects. Lastly, other variants, called pathogenic mutations, cause diseases, like Smith-Kingsmore syndrome.
Furthermore, if WES detects a likely pathogenic variant of MTOR, the parents should also undergo testing. This can determine if one of the parents carries the same variant. If a healthy parent carries the variant, it is unlikely to be pathogenic.
Whole Genome Sequencing
Because most mutations known to cause disease occur in exons, WES is an efficient method. Researchers have successfully used it to identify MTOR variants. However they have also found that DNA variations outside the exons can affect gene activity and protein production. These variations can lead to genetic disorders, which WES would miss. Therefore researchers can also use another method, called whole genome sequencing.
WGS determines the order of all the nucleotides in an individual’s DNA. It can determine variations in any part of the genome. Likewise WGS can also identify MTOR variants.
More Information
To learn more about a diagnosis of Smith-Kingsmore syndrome, please check out the What Is SKS? (MTOR gene), or SKS Research Updates page. For more information on WES and WGS testing, please check out the National Library of Medicine, which describes these tests in more detail.
