The Rapidly Expanding Genetic Spectrum of Common Variable Immunodeficiency-Like Disorders.

Rohan Ameratunga, Emily S J Edwards, Klaus Lehnert, Euphemia Leung, See-Tarn Woon, Edward Lea, Caroline Allan, Lydia Chan, Richard Steele, Hilary Longhurst, Vanessa L Bryant

Journal: The journal of allergy and clinical immunology. In practice 2023;11(6):1646-1664

PMID: 36796510

Full Text on Elsevier Science View on PubMed

Abstract

The understanding of common variable immunodeficiency disorders (CVID) is in evolution. CVID was previously a diagnosis of exclusion. New diagnostic criteria have allowed the disorder to be identified with greater precision. With the advent of next-generation sequencing (NGS), it has become apparent that an increasing number of patients with a CVID phenotype have a causative genetic variant. If a pathogenic variant is identified, these patients are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder. In populations where consanguinity is more prevalent, the majority of patients with severe primary hypogammaglobulinemia will have an underlying inborn error of immunity, usually an early-onset autosomal recessive disorder. In nonconsanguineous societies, pathogenic variants are identified in approximately 20% to 30% of patients. These are often autosomal dominant mutations with variable penetrance and expressivity. To add to the complexity of CVID and CVID-like disorders, some genetic variants such as those in TNFSF13B (transmembrane activator calcium modulator cyclophilin ligand interactor) predispose to, or enhance, disease severity. These variants are not causative but can have epistatic (synergistic) interactions with more deleterious mutations to worsen disease severity. This review is a description of the current understanding of genes associated with CVID and CVID-like disorders. This information will assist clinicians in interpreting NGS reports when investigating the genetic basis of disease in patients with a CVID phenotype.

Address: Department of Clinical immunology, Auckland Hospital, Auckland, New Zealand; Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand; Department of Molecular Medicine and Pathology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address: [email protected].; The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, and Allergy and Clinical Immunology Laboratory, Department of Immunology, Monash University, Melbourne, VIC, Australia.; Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre, School of Biological Sciences, University of Auckland, Auckland, New Zealand.; Auckland Cancer Society Research Centre, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand.; Department of Clinical immunology, Auckland Hospital, Auckland, New Zealand.; Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand; Department of Respiratory Medicine, Wellington Hospital, Wellington, New Zealand.; Department of Medicine, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Department of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC, Australia.

DOI: 10.1016/j.jaip.2023.01.048

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MeSH Terms: Humans, Common Variable Immunodeficiency, Mutation, Phenotype, Agammaglobulinemia