Background/Purpose: Lupus is a complex heterogeneous disease, which can affect almost any organ system. The genetic etiology of lupus is complex, with multiple genetic susceptibility loci identified. Monogenic lupus, caused by a specific single gene defect, is less common but is generally characterized by early disease onset and more severe presentation. The aim of this study was to understand the genetic basis of a consanguineous family with multiple lupus affected siblings in order to gain insights into lupus pathogenesis.

Methods: DNA samples extracted from whole blood were obtained from all members of a family of 13 (11 siblings and their parents) with 3 sisters affected by early-onset lupus with renal and central nervous system complications. Whole exome sequencing was performed for the 3 affected sisters and both parents. Because of strong consanguinity between both parents (first degree cousins both from their paternal and maternal descents), we assumed a recessive genetic model and focused on identifying rare recessive variants in the affected sisters that are present in heterozygous forms in both parents. Variants were filtered for potentially protein damaging effects using SIFT, Polyphen2, MutationTaster, Mutation Assessor, and FATHMM functional prediction algorithms. Sanger sequencing and Sequenom genotyping were used for validation and genotyping all unaffected siblings.

Results: Using whole exome sequencing, we found that each sister has multiple rare recessive mutations, including rare predicted damaging coding mutations in genes such as FAS, RAD51B, and ISG15, involved in apoptosis, DNA damage repair, and interferonopathy, respectively. These recessive genotypes are exceedingly rare in the general population with expected frequencies of ~1, 9, and 3 in 100,000 individuals, respectively. Interestingly, these mutations were mutually exclusive in the affected sisters. While the ISG15 recessive mutation was not present in any unaffected sibling, homozygosity for the FAS and RAD51B mutations were not sufficient to explain lupus in the two other affected sisters as some of the unaffected siblings also have these recessive genotypes. Multiple other rare recessive variants enriched in genes related to apoptosis, inflammasome activation, and cell cycle regulation were identified in the affected sisters, suggesting that accumulation of multiple rare recessive variants underlies lupus phenotype in this family. Indeed, calculating genetic risk score using the total of 69 rare recessive variants identified in the affected sisters revealed a significantly higher genetic risk (~2 times) in the affected compared to unaffected siblings.

Conclusion: We describe a unique genetic model in a consanguineous family with lupus whereby the additive effect of a number of rare recessive variants in inflammatory pathways likely contributes to the disease phenotype within the same family.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exome-sequencing-reveals-rare-recessive-mutations-in-multiple-genes-including-fas-rad51b-and-isg15-in-a-single-family-with-lupus-and-suggests-a-unique-genetic-model/