Clinical and population genetic insights into primary complement component 2 (C2) deficiency: A founder variant in...

Complement component 2 deficiency (C2D) is the most common inherited complement deficiency and is associated with severe bacterial infections and autoimmunity. We describe a 14-year-old Ashkenazi Jewish boy presenting with bullous cutaneous lupus erythematosus and lupus nephritis, whose diagnosis of C2D was prompted by a family history of fatal pneumococcal meningitis in a sibling. Genetic analysis identified homozygosity for the recurrent C2 c.841_849 + 19del variant, and complement studies confirmed absent classical pathway activity and profoundly reduced C2 levels. Population analysis of approximately 33,000 exomes from the Hadassah Medical Center database demonstrated marked enrichment of the variant among Ashkenazi Jews, with an estimated carrier frequency of ∼3%, whereas the variant was rare in Mizrahi Jews and not detected among Israeli Arabs in our cohort. These findings support a founder effect in the Ashkenazi Jewish population and suggest that C2D may be substantially underdiagnosed.