A novel IKZF1 variant in a family with autosomal dominant CVID: A case for expanding exon coverage in inborn errors of immunity.

Autor: Stojkic I; Division of Pediatric Rheumatology, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address: Ivana.Stojkic@nationwidechildrens.org., Prince BT; Division of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, USA., Kuehn HS; Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA., Gil Silva AA; Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA., Varga EA; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA., Rosenzweig SD; Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA., Ramadesikan S; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA., Supinger R; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA., Marhabaie M; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA., Chang P; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA., Mardis ER; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA., Koboldt DC; Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
Jazyk: angličtina
Zdroj: Clinical immunology (Orlando, Fla.) [Clin Immunol] 2024 Jul; Vol. 264, pp. 110244. Date of Electronic Publication: 2024 May 09.
DOI: 10.1016/j.clim.2024.110244
Abstrakt: Common variable immune deficiency (CVID) is a heterogenous group of disorders characterized by varying degrees of hypogammaglobulinemia, recurrent infections, and autoimmunity. Currently, pathogenic variants are identified in approximately 20-30% of CVID cases. Here we report a 3-generation family with autosomal dominant Common Variable Immunodeficiency (CVID) diagnosed in 9 affected individuals. Although primary immune deficiency panels and exome sequencing were non-diagnostic, whole genome sequencing revealed a novel, pathogenic c.499C > T: p.His167Tyr variant in IKZF1, a critical regulator of B cell development. Functional testing done through pericentromeric heterochromatin localization and light shift chemiluminescent electrophoretic mobility shift assay confirmed the variant's deleterious effect via a haploinsufficiency mechanism. Our findings expand the spectrum of known IKZF1 mutations and contribute to a more comprehensive understanding of CVID's genetic heterogeneity. Furthermore, this case underscores the importance of considering whole genome sequencing for comprehensive genetic diagnosis when concern for a monogenic inborn errors of immunity is high.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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