Single-centre comparison of non-familial, familial and monogenic lupus.

Objective: There is a significant genetic contribution to systemic lupus erythematosus (SLE). Monogenic SLE is a distinct form of SLE. We investigated whether familial or known monogenic lupus cases are distinguishable from non-familial lupus by clinical or laboratory phenotype in a population with high rates of consanguinity.

Methods: We performed a retrospective case-control study on 24 multiplex families, comprising 62 cases, and 95 non-familial lupus controls. Demographic and Systemic Lupus International Collaborating Clinics criteria were compared between the two groups. Familial cases were also evaluated by whole exome sequencing and cellular phenotyping. Statistical analysis was performed using R Studio.

Results: Familial and non-familial lupus cases were similar although familial cases were younger at presentation (18 y vs 26 y, OR = 0.91, p= 1.61x10-5), a higher prevalence of synovitis (OR = 2.7, p= 0.013) and lower prevalence of high level of dsDNA antibodies (OR = 0.25, p= 1.9x10-3). Exome sequencing of a subset yielded a diagnostic rate of 36%. Monogenic lupus were distinguished from other familial cases by an even younger age at presentation (6 y vs 19 y, OR = 0.82, p = 2.13 x10-3), non-biased male to female ratio (p = 0.077) and expansion of exhausted CD4+ T cells (CD4+CD45RA+PD-1+) (p = 1.7x10-4).

Conclusions: Overall, clinical phenotype is a poor indicator of familial or monogenic lupus. Familial lupus and monogenic familial lupus (MoFL) tend to present at a younger age than the Non-MoFL, exhibit less female bias, and in some cases, are distinguished by a lymphocyte signature. Consanguinity increases the rate of monogenic familial lupus, and these cases can present in adulthood.