Genetic landscape of early-onset systemic lupus erythematous in India

To investigate the genetic basis of early-onset systemic lupus erythematosus (EOSLE) in a large Indian pediatric SLE (pSLE) cohort.

This prospective observational study investigated monogenic causes in 97 of 365 pSLE patients. Inclusion criteria for the study comprised patients with EOSLE (age ≤8 years) and/or those with a clinical suspicion of monogenic lupus. Monogenic cause was suspected in 97 patients. Genetic screening using targeted next-generation sequencing on the Ion S5 system in 55 of 97 patients [complement defect gene panel in 28 and type 1 interferonopathy gene Interferon (IFN)+ Adaptive Immunity panel in 27] was performed. The remaining 42 patients underwent whole-exome sequencing (WES).

Among 97 patients, 22 (22.68%; 11 boys and 11 girls) were found to carry pathogenic variants. Median symptom onset in monogenic cases was 2 years (range: 2 months to 9 years). Monogenic lupus was identified in both EOSLE and older children with strong clinical suspicion. EOSLE patients showed a higher diagnostic yield (28.4%) compared with older children (4.4%). Consanguinity was reported in 7/22 (31.8%) patients. Variants were found in C1QA (n = 7), C1QC (n = 2), C1QB (n = 1), C1R (n = 1), C3 (n = 2), ACP5 (n = 2), STING1, DNASE2, ADAR, TREX1, DNASE1L3, PEPD and SLC7A7 (each n = 1).

Monogenic causes were found in at least 6.1% of the overall cohort of pSLE and in 22.7% of genetically screened cases, with the highest yield in EOSLE (28.4%). C1QA was the most common single-gene defect (7.2%). These findings underscore the value of genetic testing in pSLE, especially those with EOSLE or suggestive clinical features.