Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by a global deficiency of glycosylphospatidyl inositol-anchored proteins (GPI-APs) on the membrane of all cell types derived from the affected stem cell. 1 The corresponding clinical phenotype results from the deficiency of GPI-AP on individual cells, and includes a triad of intravascular hemolytic anemia, propensity for thrombosis and bone marrow failure inherently linked to the properties of the affected stem cell. Although the PNH phenotype is non-malignant, outgrowth of GPI-AP (–) clones is mediated by a selective advantage in the context of a permissive condition, such as autoimmune-mediated bone marrow suppression as seen in aplastic anemia. 2 The GPI-AP (–) phenotype results from mutations of the PIG-A gene, located at Xp22. 2, which participates in GPI synthesis. 3 Because the gene is X-linked, a single frame-shift or missense inactivating mutation results in loss of GPI-AP expression on the cell surface and because of the X-chromosome inactivation, the frequency of PNH is similar in men and women. New cytogenetic technologies, such as single-nucleotide polymorphism array-based karyotyping, show superb resolution allowing for detection of submicroscopic chromosomal defects not seen on metaphase spreads. 4 We have systematically applied this technology to identify clonal aberrations in patients with various forms of bone marrow failure. 5 During this molecular screen, a microdeletion of Xp22. 2, encompassing the PIG-A locus, was found in three patients with PNH. We have shown that in addition to PIG-A mutations, PNH results from clonal deletion of chromosomal material, likely leading to the same selective clonal advantage as hypomorphic mutation of the PIG-A gene. The initial observation was made through analysis of a 51-year-old male whose initial presentation of PNH included a thrombotic event (patient# 1). The workup of thrombophilia included testing for PNH using flow cytometry; the patient showed diagnostic GPI-AP (–) granulocytes and mild intravascular hemolysis (Figure 1a, left). On the basis of these findings a diagnosis of a classic PNH was made. Additional testing showed the presence of a JAK2V617F mutation. Laboratory workup included sequencing of PIG-A mRNA in sorted GPI-deficient and normal granulocytes. However, PNH granulocytes yielded no PIG-A complementary DNA amplification product and quantitative PCR demonstrated a lack of PIG-A amplicons from the GPI-AP (–) granulocytes using the normal cell population as the calibrator (Figure 1a, center). This peculiar finding led to the review of single-nucleotide polymorphism array karyograms from sorted PNH and normal granulocytes; a microdeletion of the PIG-A locus at Xp22. 2 was identified in PNH cells while normal cells had an intact X chromosome, confirming the somatic nature of the microdeletion (Figure 1a, right). The microdeletion spanned 555kb from bases 15189545 to 15744107 and included the genes