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.

Clinical and laboratory phenotypes in juvenile-onset Systemic Lupus Erythematosus across ethnicities in the UK

“…the absence of autoantibodies), and/or increased disease activity which can change over time to a more classical picture mimicking jSLE. 6 , 32 Thus, differences between ethnicities may be somewhat age dependent. Indeed, later during the disease course, disease activity (as measure by SLEDAI and pBILAG) did not vary significantly between ethnicity groups.…”

Type I Interferonopathies in Children: An Overview

“…Recently, childhood-onset SLE was linked to single-gene mutations, defining monogenic or familiar SLE. This evolving monogenic mutations can be grouped into four classes: (I) complement factors, (II) enzymes involved in the endogenous metabolism of nucleic acids (extracellular DNASE), (III) proteins directly involved in IFN type I pathway, and (IV) factors involved in the regulation of B and T lymphocyte self-tolerance ( 69 – 71 ). Main genes involved in these forms are summarized in Table 2 .…”

“…OTUD1 gene encodes for a deubiquitinase that interacts with IRF3, removing the poly-ubiquitin chains on IRF3 and suppressing IFN gene transcription. Patients with loss-of-function missense mutations in OTUD1 present with many different autoimmune disease, including early onset-SLE ( 71 ).…”

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review

“…Tartrate-resistant acid phosphatase (TRAP) deficiency in SPENCD predisposes patients to develop SLE, mostly starting during childhood [12,13]. The probability of a monogenic etiology increases with the decreasing age of onset in SLE [14], and SPENCD is a one of the rare causes of monogenic forms of SLE. Here, we present two siblings with a diagnosis of SPENCD, who had juvenile-onset SLE.…”