Case Report: Novel splicing mutations in RFX5 causing MHC class II deficiency

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Mutations in Regulatory Factor X5 (RFX5) are linked to autosomal recessive major histocompatibility class II (MHC-II) deficiency, a severe immunodeficiency.
• MHC-II deficiency disrupts cellular and humoral T-cell responses due to impaired MHC-II expression, affecting antigen presentation.

Observation:

• An infant with severe immunodeficiency presented compound heterozygous splicing mutations in RFX5: c.353 + 6T>G (maternal) and c.757 + 1G>A (paternal).
• The c.757 + 1G>A mutation was likely pathogenic, while c.353 + 6T>G was of uncertain significance per ACMG guidelines.
• RT-PCR analysis of the mother's blood revealed that the c.353 + 6T>G mutation causes a 191-bp intronic sequence insertion (intron 6) in transcripts.

Findings:

• The intronic sequence insertion resulted in a frameshift and premature truncation of the RFX5 protein.
• This truncation significantly affected the DNA-binding domain (DBD) of the RFX5 protein, impairing its function.
• The study confirmed the pathogenicity of the RFX5 c.353 + 6T>G mutation.

Implications:

• These findings expand the known spectrum of pathogenic mutations causing MHC-II deficiency.
• The results provide valuable insights for genetic counseling, prenatal diagnosis, and preimplantation genetic testing for this severe immunodeficiency.