A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

A heterozygous AICDA nonsense variant, c.589G>T (p.G197*), truncating the final two C-terminal residues, is linked to adult-onset HIGM2 with a complete CSR block and ~10-fold SHM reduction.

• Why it matters: HIGM2 stems from impaired AID-dependent antibody diversification, but the functional impact of extremely small C-terminal truncations and whether B-cell culture systems can restore activity is unclear.
• What they did: Single-cell sequencing of primary patient B cells showed complete CSR failure and ~10-fold reduced SHM; AID protein was reduced to ~56% despite balanced mRNA and normal localization, and iGB cultures rescued CSR.
• The result: Inducible germinal center cultures restored CSR in purified naive patient B cells and in CRISPR-Cas9–edited healthy donor B cells with heterozygous, but not homozygous, AICDA variants.

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