Centre for Genomic & Experimental Medicine
Centre for Genomic & Experimental Medicine

Dissection of the genetic basis of childhood lupus

A large genetic panel analysis published in Lancet Rheumatology provides important new insights into the molecular architecture of childhood-onset lupus. January 2020

Genetic testing

Systemic lupus erythematosus (SLE) is a rare immunological disorder characterized by the presence of autoantibodies targeting nuclear autoantigens, and by type I interferon upregulation. Familial aggregation, and higher concordance rates between monozygotic (20 – 40%) relative to dizygotic twins and other full siblings (2 – 5%), suggest a major hereditary component to SLE pathogenesis. Whilst genome-wide association studies (GWAS) have identified more than 90 loci as robustly associated with the lupus phenotype, it is an overlooked fact that Mendelian forms of lupus have been described in the context of almost 30 discrete genotypes in humans, and more than 60 single gene defects in mice.

To address the issue of the genetic contribution to lupus in children, in a study funded by the European Research Council, Professor Yanick Crow and colleagues performed an analysis of 147 genes at depth, selected on the basis of their involvement in lupus pathogenesis, in 117 unrelated probands with SLE demonstrating onset before the age of 16 years. Within the gene set previously associated with monogenic forms of SLE, they observed mutant genotypes to be present in 7% of probands. Furthermore, heterozygous, predicted pathogenic variants in genes previously implicated in lupus causation from GWAS and animal models were significantly enriched in the SLE cohort compared to controls. Of further interest, the results from this study support the concept of oligogenicity in SLE genetic susceptibility, with an accumulation of rare, predicted pathogenic variants in different genes in patients.

Numerous clinical trials in SLE have failed to demonstrate a positive effect of a variety of study drugs, and current clinical and laboratory criteria are clearly not sufficient to detect specific factors determining treatment outcome. These new data are consistent with an underlying heterogeneity of the lupus phenotype, and suggest that an exploration of genetic burden in single individuals may be informative in tailoring future personalized therapeutic interventions.

Prof. Yanick Crow


Article in journal Lancet Rheumatology https://doi.org/10.1016/S2665-9913(19)30142-0

Prof Yanick Crow's Research Group Website