Investigating concomitant RAG-2 and LRBA mutations in SCID and autoimmunity

Area of Science:

• Immunology
• Genetics
• Medical Science

Background:

• Inborn errors of immunity (IEI) encompass diverse conditions with immunodeficiency, immune dysregulation, and increased malignancy risk.
• Most IEIs follow an autosomal recessive inheritance pattern.
• Severe combined immunodeficiency (SCID) with Omenn phenotype presents early and requires intensive management.

Purpose of the Study:

• To investigate the genetic basis of severe immunodeficiency and immune dysregulation in a patient with a consanguineous background.
• To characterize the immunological profile and genetic mutations contributing to complex IEI.
• To evaluate the pathogenicity of identified genetic variants through functional assays.

Main Methods:

• Collected clinical, immunological, and genetic data from the patient.
• Performed whole exome sequencing on fibroblast DNA and Sanger sequencing for family segregation.
• Conducted lymphocyte evaluation, chimerism analysis post-hematopoietic stem cell transplantation (HSCT), and flow-cytometry for Treg subsets, LRBA, and CTLA4 expression.

Main Results:

• Identified bi-allelic homozygous mutations in RAG-2 and a novel LRBA variant (c.3325G>T, p.Asp1109Tyr).
• Normal LRBA and CTLA4 expression suggested the identified LRBA variant is likely non-pathogenic.
• The patient presented with SCID and later developed severe autoimmune phenomena despite HSCT.

Conclusions:

• Individuals in consanguineous populations can harbor multiple distinct genetic defects causing complex IEI.
• Functional immunological testing is crucial for assessing the pathogenicity of newly discovered genetic variants in IEI.
• This case underscores the diagnostic challenges and importance of comprehensive genetic and immunological evaluation in refractory IEI.