Familial GPS. (A) This pedigree reflects the X-linked pattern of inheritance that was suspected clinically and later confirmed by DNA analysis. Subject I-A was diagnosed with idiopathic thrombocytopenic purpura (ITP) in childhood and died of complications of chronic myelogenous leukemia. His medical record contains frequent references to his abnormally large platelets. Subject III-A has been extensively evaluated for his history of chronically low platelets without a definitive diagnosis. Subject III-D had a splenectomy to manage persistent thrombocytopenia. ▪, affected; ▨, carrier; ▪, inferred from clinical history; ⋄, not tested; □, not affected; ☆, proband. (B) The proband's blood smear (IV-M) contains normal-appearing platelets and a population of abnormally large, pale, agranular platelets (arrowheads). A blood smear from the proband's father (III-S) contains decreased platelets, and those present have similarly abnormal morphology. (C) Electron micrograph (EM) of a peripheral blood platelet from subject III-S shows a large platelet with enlarged elements of the open canalicular system and the virtual absence of α-granules. The α-granules that are present lack the characteristic electron density, appearing “empty.” Scale bar, 1 μm. Original magnification, 35 100×. A range of platelet EM morphologies was seen in this individual and his brother (subject III-Q), including some platelets with more abundant, better-formed α-granules (Figure S2). (D) DNA sequencing of GATA1 exon 4 demonstrated a G-to-A transition segregating with the phenotype and predicted to result in an arginine-to-glutamine change at amino acid 216 (R216Q).