Complete and partial forms of X-linked MCTS1 deficiency in patients with mycobacterial disease.

X-linked recessive (XR) complete MCTS1 deficiency underlies Mendelian susceptibility to mycobacterial disease (MSMD) in patients with bacille Calmette-Guérin (BCG) disease. We investigated the genotypic and phenotypic landscape of four new unrelated families from four distinct countries. Three patients had adverse reactions to the BCG vaccine, whereas another patient was not vaccinated with BCG and had an infection with at 16 years of age. Whole-exome sequencing of the probands revealed hemizygosity for rare germline variants. In addition to a previously reported loss-of-expression (LOE) and loss-of-function (LOF) variant, we identified three new variants. The p.L170* and E60Kfs5* variants are LOF, whereas p.W175* is hypomorphic when overexpressed. Thus, we report four new MSMD patients with complete or partial forms of XR MCTS1 deficiency, including three patients with newly discovered genotypes. A diagnosis of partial or complete XR MCTS1 deficiency should be considered in boys and men with MSMD displaying mycobacterial infection.© 2026 Zhou et al.