Submissions for variant NM_006060.6(IKZF1):c.584A>G (p.His195Arg)

dbSNP: rs1131690788

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Immunogenetics Laboratory, Johns Hopkins All Children's Hospital	RCV000492439	SCV000576413	pathogenic	Pancytopenia due to IKZF1 mutations	2017-04-05	criteria provided, single submitter	clinical testing	Mutations in the transcription factor IKAROS (encoded by IKZF1) cause an autosomal dominant antibody deficiency (infections, progressive loss of B cells and immunoglobulins [Ig]). Cytopenia and leukemia may occur. We report a teenager who presents with chronic severe immune thrombocytopenia (ITP) and low serum IgG, IgA, and IgM since age 3. His mother also had low IgG and at age 23 had ITP requiring splenectomy. Neither had frequent infections. Patient and his mother had a novel heterozygous missense mutation in the DNA binding motif zinc finger 3 of IKZF1 (c.584A>G, p.His195Arg). In vitro studies of mutant IKAROS showed loss of characteristic pericentromeric DNA-binding (arrow), consistent with previous findings of other pathogenic mutations (H167R) in IKZF1. IKAROS deficiency may present with ITP in the absence of infections. For ITP patients, we recommend serum Ig screening and evaluation for antibody defects. Identifying the genetic diagnosis in these cases can help anticipate complications in patients and their families.