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

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Inborn errors of immunity (IEI) are typically monogenic disorders caused by germline variants.
• Increasing evidence suggests acquired somatic variants can also lead to IEI or mimic its symptoms.
• Somatic mosaicism is often discovered in sporadic IEI cases with autoinflammation or autoimmunity when germline variants are absent.

Purpose of the Study:

• To review the current understanding of somatic mosaicism in IEI.
• To discuss the challenges and methodologies for detecting somatic variants.
• To explore diagnostic approaches for molecularly diagnosing patients with somatic mosaicism-related IEI.

Main Methods:

• Literature review of studies on somatic mosaicism and IEI.
• Analysis of diagnostic approaches for low-level variant detection.
• Discussion of genetic variants identified in IEI, including in genes like FAS, UBA1, and TLR8.

Main Results:

• Somatic mosaicism is an emerging cause of IEI, affecting genes known for germline IEI and novel genes.
• Detection of low-level somatic variants presents significant technical challenges.
• The full extent of somatic mosaicism in IEI remains largely uncharacterized.

Conclusions:

• Somatic mosaicism is a critical, albeit under-recognized, contributor to IEI.
• Advanced molecular diagnostic techniques are essential for identifying somatic variants.
• Further research is needed to fully elucidate the role and prevalence of somatic mosaicism in immune disorders.