Bi-allelic TTC21A mutations in common variable immunodeficiency patients

Abstract Very little is known about the gene TTC21A – it was first described as a gene in the AP20 sub-region of chr3p.21.3 in which deletions were associated with cancer. Initially, TTC21A mRNA expression was only found in the testis, consistent with a recent study linking homozygous TTC21A mutations to decreased fertility due to structural defects in sperm flagella. Interestingly, the gene is also expressed in B lymphocytes with several smaller predicted protein coding transcripts enriched particularly in naïve and memory B cells. Here we report four individuals of one kindred with common variable immunodeficiency (CVID) with two different sets of rare biallelic TTC21A variants. Based on whole genome sequencing analysis, TTC21A was the only candidate gene that co-segregated with disease across three generations and eight individuals of this family with an autosomal recessive mode of inheritance. The affected individuals had low serum IgG and a significant defect in class-switching. In-depth B cell immunophenotyping revealed that, relative to healthy family controls, the patients had significant skewing of increased transitional (CD27− IgD+ CD24+ CD38+) B cells and markedly reduced terminally differentiated plasmablasts (IgD− CD20low CD38+). The patients with the rare homozygous variant also had significantly reduced expression of the B cell specific TT21A variant relative to the family controls and patients with the compound heterozygous variants. Initial immunization experiments of Ttc21a CRISPR knock-in mice mirrored the patients’ phenotype with decreased class switching; however subsequent repeats have been inconclusive. Additional work is necessary to further elucidate the immune function of TTC21A in B cells. Supported by the NIH Oxford-Cambridge MD/PhD Scholarship