Perspective: Application of the American College of Medical Genetics
variant interpretation criteria to Common Variable Immunodeficiency
Disorders
Abstract
Common Variable Immunodeficiency Disorders (CVIDs) are rare Primary
Immunodeficiency diseases (PIDs) associated with late onset antibody
failure leading to immune system failure. Most patients suffer recurrent
and severe infections, while some have predominantly autoimmune and
inflammatory disorders. In recent years a large number of genetic
defects have become associated with these disorders. Next Generation
Sequencing (NGS) allows the analysis of multiple genes simultaneously.
The mutations identified from NGS are evaluated with the American
College of Medical Genetics (ACMG) variant interpretation criteria to
determine their pathogenicity (causality). We have advocated all
patients with a CVID phenotype should undergo genetic testing but
acknowledge the complexity of the genetics associated with these
disorders. Variants of Unknown Significance (VUS) remain a significant
barrier to realising the full potential of NGS in CVID and CVID-like
disorders. We review the nuances of the application of the ACMG variant
interpretation criteria to patients with a CVID phenotype.