“What we are learning is that even some diseases not considered [to be] genetic could be associated with monogenic SM occurring later in life,” says Dr. Hoffman. “Diseases like rheumatoid arthritis or lupus are assumed to be complex diseases and not solely genetic in etiology, because they present when patients are in their 30s, 40s or 50s. It opens our eyes to the possibility that these diseases may actually be related to somatic mutations in specific genes, which has important implications for how we diagnose, treat and counsel patients.”
An example of how SM can impact disease diagnosis and treatment was recently published in i.1 The case study described a male infant with a clinical presentation typically seen in neonatal-onset multisystem inflammatory disease (NOMID).
Exome sequencing failed to identify pathogenic variations in the NLRP3 gene, which occurs in a substantial percentage of NOMID patients. However, the group subsequently evaluated the child’s entire genome and found a somatic mutation in the NLRC4 gene, which can have a presentation similar to patients with NLRP3 mutations. In this patient, only a small percentage of cells carried the NLRC4 mutation, but this was enough to create systemic symptoms affecting the entire body.
“Even with standard genetic sequencing you don’t always get the information you need,” says Dr. Hoffman. “This is where advances in next generation sequencing [NGS] will make a real difference.”
Next Generation Sequencing Next Big Step
NGS is a genetic sequencing method that can examine multiple parts of our genetic material repeatedly. Similar to a movie set that uses several cameras from different angles, we have multiple views of the same scene. From one view, we may see only the actress, but from another camera, the audience can view the entire cast. At a genetic level, this means that a scientist can analyze a mixed population of cells with different mutations, but it is still not a 100% guarantee that a mutation will be found.
“Even with NGS, we may still miss somatic mutations that are very rare,” says Dr. Hoffman. “If the mutation is occurring in a very small percentage of your cells, or not at all in the blood, which is tested most often, you may need to do alternative sequencing methods or obtain multiple samples from different tissues or cells to find where the mutation is expressed. It may take a skin sample or sperm specimen to identify somatic mosaicism in different tissues.”
Knowledge Base Lacking
Although Dr. Hoffman notes some intriguing hints of the potential impact SM may have on diagnosis and treatment of rare autoinflammatory disorders, the knowledge base is still lacking. Much of the literature has been in the form of case studies.
