The first tool to diagnose any genetic condition is clinical suspicion. Smith-Kingsmore syndrome is a rare condition, not yet known by many clinicians, however the initial diagnosis is based on clinical manifestations. After completing a physical examination and collecting a detailed medical family history, if a doctor suspects Smith-Kingsmore syndrome, genetic testing will be the next step to confirm.
The confirmation of Smith-Kingsmore syndrome can be made through one of two genetic tests: Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS). As described at the National Library of Medicine (https://ghr.nlm.nih.gov/primer/testing/sequencing), whole exome sequencing and whole genome sequencing are increasingly used in healthcare and research to identify genetic variations. Both methods rely on new technologies that allow rapid sequencing of large amounts of DNA. These approaches are known as next-generation sequencing (or next-gen sequencing).
Whole Exome Sequencing
With next-generation sequencing, it is now feasible to sequence large amounts of DNA, for instance all the 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. Together, all the exons in a genome are known as the exome, and the method of sequencing them is known as whole exome sequencing. This method allows variations in the protein-coding region of any gene to be identified, rather than in only a select few genes.
WES detects genetic spelling errors, called variants, in genetic sequence. Some variants are benign (they do not cause disease). Some variants have uncertain effects (they are called variants of unknown significance). Other variants are known to cause disease (they are called pathogenic mutations). Pathogenic mutations of MTOR are associated with Smith-Kingsmore syndrome.
If a likely pathogenic variant of MTOR is detected, the parents should also undergo WES to determine if one of the parents carries the same variant. If the variant is present in a healthy parent, it is unlikely to be pathogenic.
Whole Genome Sequencing
Because most known mutations that cause disease occur in exons, whole exome sequencing is thought to be an efficient method to identify possible disease-causing mutations, and has been successfully used to identify MTOR variants. Researchers have found that DNA variations outside the exons can affect gene activity and protein production and lead to genetic disorders, variations that whole exome sequencing would miss. Another method, called whole genome sequencing, determines the order of all the nucleotides in an individual’s DNA and can determine variations in any part of the genome. WGS can also be used to identify MTOR variants.