Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation.
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New methods of gene sequencing have resulted in improved identification of mutations in patients and increased availability of genetic testing in rare diseases. Despite these exciting advances, a majority of patients lack identifiable mutations and the underlying disease etiology remains an enigma. Somatic mosaicism (SM) may be an explanation for some of these clinically challenging patients.
“The concept of SM is actually a bit odd when you think about it,” said Hal Hoffman, MD, from the University of California, San Diego. “Instead of mutations being passed on from parent to child, or happening in the sperm or egg, the mutation occurs as the embryo is developing, or even after birth. What you end up with is an individual that can have different DNA or different mutations in different cells—a genetic smorgasbord.”
Not a New Concept
Somatic mosaicism is not a new concept. It is more easily recognized in the skin, when the mutation affects skin coloring, causing some areas of skin to appear dark in pigmentation and other areas lighter in color.
“In these cases, the mosaicism happens in just one particular type of tissue or cell,” said Dr. Hoffman. “For other patients, it can occur in a subset of those cells and span a number of tissues, often leading to larger effects.”
This variability in expression can complicate genetic diagnosis of diseases. For example, if the tissue sampled for genetic testing, typically blood or saliva, is not expressing the mutation, a patient may appear to not carry the mutation: the equivalent of a false negative.
SM Can Occur at Any Age
Further complicating genetics, SM mutations may occur at any age. Therefore, an individual appearing to have late-onset disease may have simply had too few cells expressing the mutation in early life to generate symptoms.
Although not often discussed, mosaicism is not a novel concept to immunologists and is an important characteristic of an effective immune system. Somatic rearrangement results in the normal diversity of immunoglobulin and T cell receptor genes, necessary for keeping individuals safe from ever-evolving infections.
However, SM has key detrimental aspects, as well, and has long been recognized in cancer with daughter cells genetically different from each other and from host cells. More recently, researchers have begun to recognize the implications of SM in autoinflammatory syndromes.
Reason for Atypical Presentations?
In the already rare autoinflammatory syndromes, SM may result in atypical presentations of diseases. In addition, the rarity of the mutant cells in some patients makes it easy to miss these infrequent changes using current genetic testing technologies. Further complicating diagnosis is the fact that these mutations can happen later in life, so patients may not show symptoms until middle age or beyond.
“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.
“Despite having the same mutation, SM patients may not look like a typical patient with that mutation and may have different symptoms,” he says. “I suspect as we reassess patients with ‘negative genetic tests,’ we’ll realize that SM is much more important than we previously thought.”
Although these findings offer genetic diagnoses to patients with difficult to diagnose diseases, an ongoing impediment to the widespread use of tests for SM is their high cost, especially for NGS. Insurance companies and federal programs are often hesitant to pay for even simple genetic tests, let alone deep NGS sequencing in multiple tissues.
Together, these issues have critical implications for treatment. Patients with unusual presentations and different symptoms from what are typically seen may not be able to get insurance approval for certain medications.
For example, Dr. Hoffman noted that many autoinflammatory disease patients, with or without identified genetic mutations, respond favorably to anti-interleukin 1 therapy. Yet rheumatologists know that many rheumatoid arthritis patients don’t find therapeutic improvement with this class of FDA-approved drugs.
Perhaps those patients who do find success are those who have a somatic mosaic mutation in genes related to autoinflammatory diseases. This might make them more likely to be responsive to the therapy. Identifying these patients and evaluating their genes in different cells or tissues may bring us closer to practicing more personalized medicine.
“We are at a very interesting time right now where the gene sequencing technology is available, and the cost is coming down at an amazingly fast rate,” says Dr. Hoffman. “As we learn more, we may find a place for more widespread application for SM testing for patients who present with uncommon manifestations or late onset disease.”
Kurt Ullman has been a freelance writer for more than 30 years and a contributing writer to The Rheumatologist for 10 years.
Reference
- Kawaski Y, Oda H, Ito J, et al. Pluripotent cell-based phenotypic dissection identifies a high-frequency somatic NLRC4 mutation as a cause of autoinflammation. Arthritis Rheumatol. 2017;69:447–459.
