AR ITK deficiency with TB. (A) Pedigree of the kindreds. Black symbols indicate affected individuals. Arrows indicate the probands. Genotypes for ITK are also shown. M, mutated. (B) Cranial T2-weighted MRI for P1. The high-intensity lesion in the right temporal lobe disappeared after 9 mo of anti-TB therapy (post-tx). (C) Surgical biopsy of an enlarged mesenteric lymph node of P1 showing central caseation on H&E staining and acid-fast bacilli (arrows) on Ziehl–Neelsen staining. (D) A thoracic CT scan of the lung of P3 showing tree-in-bud signs. Radiological improvement was observed after 4 mo of anti-TB therapy. (E) Variants detected by WES. (F) Sanger sequencing of the ITK variants. (G) Population genetics of ITK. The minor allele frequency (MAF) and CADD scores for all non-synonymous variants reported in the gnomAD database are shown. Three homozygous variants found in our private cohort are also shown. The CADD score of 35.0 for the c.496C>T (R166*) allele is well above the MSC of 20.7 (Kircher et al., 2014; Itan et al., 2016; horizontal dotted line). (H) Gene-level negative selection. Like other genes with mutations underlying AR IEI, ITK is not under negative selection, as shown by CoNeS (Rapaport et al., 2021). (I) Schematic representation of the ITK protein. PH, pleckstrin homology domain; SH, Src homology domain. Previously reported homozygous or compound heterozygous mutations are also shown.