Journal Article

All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing

Woon, See-Tarn, Ameratunga, Rohan, Lehnert, Klaus

2019

Overview

The phenotypic heterogeneity may be the result of variable penetrance and expressivity, epigenetic influences or epistasis caused by gene-gene interactions. Because of genetic and phenotypic heterogeneity, there has been understandable reluctance to routinely sequence CVID patients because of the low yield (25). Given the rapid progress in the understanding of these conditions in recent years, we believe there is now a strong case for routine diagnostic genetic testing of patients with a CVID phenotype (Table 1). Establishing the diagnosis Confirming the clinical diagnosis of a CVID-like disorder Identifying novel presentations of other CVID-like disorders eg as LOCID Identifying atypical presentations of other PIDs with hypogammaglobulinemia eg XLP Distinguishing genetic from acquired disorders eg drug-induced hypogammaglobulinemiaIdentifying digenic disordersTHA-Variability of IgG levels over time: some of these patients may have CVID-like disordersDifferences in diagnostic criteria for CVID: the presence of a CVID-like disorder will obviate the need to apply CVID diagnostic criteria.Identifying CVID-like disorders in patients who have already developed malignancyIdentifying CVID-like disorders in patients on SCIG/IVIG or immunosuppression Treatment Offering early SCIG/IVIG treatment for individuals carrying causative mutationsIdentifying specific treatment options eg abatacept for CTLA-4/LRBA deficiency Identifying patients who may benefit from gene based therapy in the future Prognosis Asymptomatic patients with monogenic defects have a high probability of symptomatic disease, leading to long-term SCIG/IVIG treatmentMay distinguish patients with THI, who may not recover till adulthood where some have impaired vaccine responses Pre-symptomatic testing Where presymptomatic diagnosis (at any age) is not possible with protein based tests eg patients with CVID-like disorders who are asymptomatic with normal immunoglobulins Diagnosis in infancy where conventional diagnostic tests are unreliable eg because of transplacentally acquired IgG levels Screening Cascade screening of at-risk relatives with or without symptoms after genetic counselingIdentifying mutations from tissue samples from deceased relativesIdentifying mutations from Guthrie cards from deceased relatives PID prevention Prenatal diagnosis with chorionic villus sampling (CVS) Pre-implantation genetic diagnosis (PGD) Research Characterizing the role of molecules in cellular function Assisting with the classification of primary immunodeficiency disorders Identification of new genetic defects with trio analysisInvestigating animal models of CVID-like disordersIdentifying epistasis caused by digenic (or oligogenic) disorders Most of the clinical scenarios are described in the text.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Asymptomatic / Common variable immunodeficiency / CTLA-4 protein / CVID - common variable immunodeficiency disorders / Epigenetics / Epistasis / Gene therapy / Genes / Genetic analysis / Genetic screening / genetic sequence analysis / Genetic testing / Genotype & phenotype / hypogammaglobinaemia / Hypogammaglobulinemia / Immune system / Immunoglobulin G / Immunoglobulins / Immunology / Immunosuppression / Intravenous administration / Kinases / Mutation / Patients / Phenotypes / Prenatal diagnosis / Primary immunodeficiencies / Proteins / transient hypogammaglobulinemia of adulthood (THA) / transient hypogammaglobulinemia of infancy / Vaccines / Villus