Haploinsufficiency for the hematopoietic transcription factor IKAROS causes common variable immunodeficiency (63.6)

Abstract

Abstract Common variable immunodeficiency (CVID) is characterized by defective immunoglobulin production that leads to recurrent infections and increased risk of autoimmune and malignant diseases. CVID is the most common primary immunodeficiency disease with an estimated 1:25,000 to 1:50,000 population frequency world-wide. Substantial progress has been made in determining the genetic basis of CVID. Mutations in ICOS, TACI, BAFF-R, CD19, CD81, CD21, and CD20, all encoding cell-surface receptors required for B-cell activation, have been found in a few individuals and families and are recognized to cause CVID. Only mutations in TACI are found frequently (both in sporadic cases and familial cases); representing 8-12 % of CVID cases. The cause of CVID is unknown in most patients (>85%). Here, we describe a large family with autosomal dominant hypogammaglobulinemia and B cell deficiency in which all affected members have a 4.7 Mb hemizygous deletion (7p12.3-p12.1) that includes IKZF1, encoding IKAROS, a transcription factor required for B-cell development. This study demonstrates that constitutional hemizygous deletion of IKZF1 leads to IKAROS haploinsufficiency, and patients with hemizygous IKZF1 deletion present with late-onset humoral immunodeficiency and low B-cell counts, complicated in one family member with pre-B-cell acute lymphoblastic leukemia requiring bone marrow transplantation.