Background/Purpose: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with multifactorial etiology. Identification of monogenic causes of pediatric SLE (pSLE) has yielded important insights into pathogenesis and can illuminate therapeutic targets. Advances in genetics have made exome sequencing accessible and integral to clinical medicine in multiple disciplines. We used exome sequencing to determine genetic causes of pSLE, aiming to identify a clinically actionable target age for sequencing pSLE patients.

Methods: We identified 48 pSLE patients at 6 centers, 41 at Texas Children’s Hospital. Patients were included if they fulfilled classification criteria for SLE and had pre-pubertal disease onset. We performed research exome sequencing (45 patients), or research reanalysis of clinical sequencing (3 patients). Results are currently available for 31 patients.

Results: Our pSLE cohort is 77% female, 25% African American/Black, and 56% White; 52% of the patients are Hispanic. The age at SLE onset was an average of 8.4 years (range 1.75-14 years). Predominant clinical features include arthritis (75%), cutaneous disease (69%), and nephritis (56%, 41% of which was Class IV). Patients were largely leuko- or lymphopenic (73%) with hemolytic anemia (60%) and hypocomplementemia (88%). Progression to end-stage renal disease occurred in 4 patients (8%), 1 patient died of disease complications.

Exome sequencing was conducted on 30 trios (including both parents), 13 duos and 5 probands only. A monogenic etiology of disease was found in 4/31 available cases (13%): COPA syndrome, RAS-associated autoimmune leukoproliferative disorder, lysinuric protein intolerance and compound heterozygous variants in DNASE1L3. The average age of disease onset for solved patients was 3.4 years. Of the 5 patients with disease onset less than 5 years of age, 3 were found to have a monogenic etiology (60%). Patients with single variants in additional SLE-associated genes (RNASEH2, SAMHD1and PRKCD) are undergoing copy number variation (CNV) analysis. Variants in complement and complement regulatory proteins are enriched in our cohort and bioinformatic analysis of the significance of this finding is underway. A novel candidate gene has been identified and is under active investigation.

Conclusion: Onset of SLE in pre-pubertal patients is uncommon, and onset in early childhood is exceedingly rare. Access to genetic testing is increasing, coupled with a growing number of elucidated genes causing pSLE. Early identification of monogenic disease can direct alternative therapies. Further, there is an impact on family planning for families with an autosomal dominant genetic disorder, as uncovered in our cohort. Therefore, sequencing patients with pSLE with an age of onset below 5 years should be an essential part of clinical care.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exome-sequencing-for-early-pediatric-systemic-lupus-erythematosus-standard-of-care-in-2020/