Acquired versus constitutional ATRX mutations. (A) Comparison of the spectrum of ATRX mutations described in boys with ATR-X syndrome with those found in ATMDS. The ATRX gene (top, with introns not to scale) is aligned with ATRX protein (bottom) to allow comparison of mutation site with functionally important protein domains such as the ADD (ie, ATRX, DNMT3, DNMT3L) zinc-finger domain (ADD includes a C2-C2 type of zinc finger and the closely located PHD motif), helicase domains, P-box, and Q-box. ATR-X–associated mutations are annotated above the schematic representation of the ATRX gene at the mutation loci, while mutations associated with ATMDS are denoted below. • represents mutations predicted to cause protein truncation (ie, frame shifts and nonsense mutations) and null mutations, whereas ○ represents amino acid changes, including in-frame insertions and deletions. Unfilled boxes denote the newly described -14G>A polymorphism and 2692G>C; D898H base-pair change of uncertain significance as described in the text. (B) Comparison of the fraction of erythrocytes containing HbH inclusions in 118 patients with ATR-X syndrome with the fraction detected in the 18 patients with ATMDS analyzed in this study. Transfused and untransfused patients with ATMDS are tallied together; the possibility of dilution by donor erythrocytes contributing to artifactually decreased HbH-containing cells in the former group should be recognized.