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Large-scale analysis of the genetic basis of pediatric systemic lupus erythematosus Abstract Background Systemic lupus erythematosus (SLE) is a rare immunological disorder where genetic factors are important in causation. Mendelian forms of lupus have been described in the context of almost 30 genotypes in humans, and more than 60 in mice. Murine susceptibility models and genome-wide association studies (GWAS) also highlight the role of genetic variants in pathogenesis. The overall genetic contribution to pediatric SLE is unknown. Methods We designed a next-generation sequencing panel comprising 147 genes, including all known Mendelian lupus causing (KLC) genes in humans, and lupus associated genes identified through GWAS and animal models (potentially lupus causing, PLC, genes). Using this panel we screened 117 probands fulfilling American College of Rheumatology criteria for SLE, ascertained through two cohorts of pediatric SLE in the UK and France, and 791 ethnically matched controls from the 1000 Genomes Project. Results Mendelian genotypes were present in 6.8% of probands. Beyond these cases, rare, predicted damaging variants were significantly enriched in the SLE cohort compared to controls, with an odds ratio of 14.09 and 3.99 in KLC and PLC genes respectively. Overall, 27% of SLE probands versus 4.6% of controls were identified with at least one rare, predicted damaging variant amongst our selected gene panel (p = 4.14×10 −15). Conclusion Rare and predicted damaging variants in KLC and PLC genes were highly enriched in a population of pediatric onset lupus, with 1 in 15 probands demonstrating clear Mendelian causation. Germline defects of innate immunity represent the main genetic contribution to SLE in children.

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia. Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.