New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Abstract

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it's prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

Keywords: SLE; complement deficiency; familial; genetic; interferon-stimulated genes (ISGs); interferonopathies; lupus; mendelian; monogenic; systemic lupus erythematosus.

Figure 1

Diagram of genes associated with monogenic systemic lupus erythematosus (SLE) and SLE-like features. The depicted genes carry novel or rare pathogenic variants that have been described in patients presenting with lupus or have either clinical or biochemical features of autoimmunity. The inner diagram includes genes associated with an upregulated type I interferon and most of these diseases are considered primary interferonopathies. The outer diagram depicts the genes that, when mutated, are associated with a spectrum of immune dysregulations and patients can manifest both features of immunodeficiency and autoimmunity. Typically, the autoimmune phenotype is milder than in patients with primary interferonopathies and there is no evidence of enhanced type I interferon signaling.