Somatic mosaicism in inborn errors of immunity: Current knowledge, challenges, and future perspectives

Abstract

Inborn errors of immunity (IEI) are a diverse group of monogenic disorders of the immune system due to germline variants in genes important for the immune response. Over the past decade there has been increasing recognition that acquired somatic variants present in a subset of cells can also lead to immune disorders or 'phenocopies' of IEI. Discovery of somatic mosaicism causing IEI has largely arisen from investigation of seemingly sporadic cases of IEI with predominant symptoms of autoinflammation and/or autoimmunity in which germline disease-causing variants are not detected. Disease-causing somatic mosaicism has been identified in genes that also cause germline IEI, such as FAS, and in genes without significant corresponding germline disease, such as UBA1 and TLR8. There are challenges in detecting low-level somatic variants, and it is likely that the extent of the somatic mosaicism causing IEI is largely uncharted. Here we review the field of somatic mosaicism leading to IEI and discuss challenges and methods for somatic variant detection, including diagnostic approaches for molecular diagnoses of patients.

Keywords: Genetics; Immunity; Inborn errors of immunity; Mosaicism; Next-generation sequencing; Primary immunodeficiency; Somatic.

Figure 1.. Genetic testing algorithm for consideration of somatic mosaicism in IEI.

Patients suspected to have an IEI based on clinical presentation and clinical laboratory testing should have genetic testing for monogenic disease. Clinical testing here refers to tests performed in a clinically-certified laboratory [e.g., CLIA (clinical laboratory improvements amendments) certification], where results are a part of the patient’s medical record and guide clinical management. Research-based testing refers to testing performed in a research-setting, with informed consent, and generally not a part of the patient’s medical record. Targeted gene panels for known IEI-associated genes are widely available for clinical testing, and can be a first-tier approach for molecular diagnosis. If panel testing does not result in a diagnosis, or as *first-line depending on availability, consider trio exome or genome sequencing, including any additional affected family members if possible (siblings). Some IEI genes (dotted line box) have incomplete coverage on NGS platforms [see (108) for additional information]. If genetic testing results in variants of uncertain significance (VUS) in an IEI-associated gene or novel gene not previously associated with an IEI, functional studies should be performed in the clinical or research testing to prove pathogenicity. Identification of additional patients with the same clinical phenotype and variants in that gene can provide additional supportive evidence. After ES or genome testing, if no relevant gene is reported, research based re-analysis or research-based exome/genome sequencing can be performed. If genetic testing fails to identify any relevant gene in a patient without family history of disease (‘sporadic’), or there is incomplete penetrance in the family [for example, some germline variants may have low clinical penetrance, and a “second hit” is required for disease onset as in somatic ALPS (20)], consider evaluation for disease-causing somatic mosaicism. If exome/genome data is available, it can be re-analyzed for somatic variants. If a somatic variant predicted to be associated with the disease phenotype is identified, the presence and variant allele frequency of the genetic variant should be validated on an orthogonal platform e.g. droplet digital PCR or amplicon deep sequencing. If the genetic variant was previously functionally validated and is consistent with known disease, the patient can be diagnosed. For novel somatic variants, functional testing should be pursued to determine pathogenicity. Figure created using Biorender (https://biorender.com/) IEI: Inborn errors of immunity; CMA: Chromosomal microarray; NGS: Next-generation sequencing; VUS: Variant of uncertain significance