Case Report: A novel homozygous splice-site variant in the C3 gene causing complete complement C3 deficiency in two unrelated Moroccan patients

Résumé

Complement component 3 (C3) plays a central role in innate immunity as a convergence point of the classical, alternative, and lectin pathways. Complete C3 deficiency is an extremely rare inborn error of immunity, typically associated with recurrent severe infections and, in some cases, immune complex-mediated or autoimmune manifestations. Despite its clinical significance, fewer than 50 cases have been reported to date, and the genetic and phenotypic spectrum remains incompletely defined. We report two unrelated pediatric patients originating from the same geographic region in Morocco, both presenting with recurrent infections. Comprehensive clinical evaluation, immunological workup including complement assays, and genetic analysis using next-generation sequencing (NGS) were performed. In silico tools were used to predict the functional impact of the identified variant, and familial segregation analysis was conducted. Both patients presented with chronic and recurrent infections, predominantly affecting the respiratory and otorhinolaryngological systems, without identification of consistent pathogens. Immunological investigations revealed normal lymphocyte subsets, immunoglobulin levels, and neutrophil oxidative burst. In contrast, complement analysis showed undetectable C3 levels and markedly reduced CH50, with normal C4, consistent with isolated complete C3 deficiency. NGS identified a novel homozygous splice-site variant in the C3 gene (NM_000064.3:c.4030-1_4030delinsCT) in both patients. The variant is absent from population databases and predicted to severely disrupt normal splicing, likely leading to loss of function. Segregation analysis confirmed heterozygous carrier status in the parents, supporting autosomal recessive inheritance. Notably, both patients originate from the same geographically confined and consanguineous region, suggesting a possible founder effect.We report two cases of complete C3 deficiency associated with a novel homozygous splice-site variant, expanding both the clinical and genetic spectrum of this rare condition. Our findings highlight that C3 deficiency may present with non-severe but chronic infections and emphasize the importance of complement evaluation in unexplained infectious phenotypes. The geographic clustering of cases raises the possibility of a founder mutation, warranting further population-based genetic studies.

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