Consanguinity and rare monogenic systemic autoinflammatory disorders: implications for prevalence and genetic variability.

backgroundSystemic Autoinflammatory disorders (SAIDs) are a group of immunedysregulation disorders driven by aberrant activation of the innate immune system, often linked to single-gene mutations. While consanguinity is a known risk factor for inherited disorders, including autoimmune diseases, its impact in the prevalence and genetic variability of SAIDs remains insufficiently explored.

objectiveTo assess the consanguinity rate among patients with SAIDs and to evaluate its impact on the prevalence and genetic variability of rare monogenic SAIDs.

methodsWe conducted a descriptive, longitudinal, observational study at the main tertiary center in Saudi Arabia. Medical records of patients with a confirmed SAIDs were retrospectively reviewed. Rare SAIDs were defined as those with ≤ 50 globally reported cases. Demographic, clinical, and genetic data of patients with rare SAIDs were collected and analyzed to assess consanguinity and its impact on prevalence and genetic variability.

resultsA total of 200 patients with SAIDs were included in this study, with data derived from the autoinflammatory disease clinic database. Consanguinity was observed in 78% of patients, while 52% had a positive family history of SAIDs. Genomic DNA sequencing was performed on 85% of the cohort, utilizing whole exome sequencing (75%), Sanger sequencing (14.7%), and targeted gene panel sequencing (9.4%). The diagnostic genetic yield revealed a confirmed monogenic etiology in 67% of the cases. The cohort encompassed various types of SAIDs, including Pyrin inflammasopathies (n = 48), other inflammasopathies (n = 20), type I interferonopathies (n = 29), NF-kB mediated SAIDs (n = 7), miscellaneous SAIDs (n = 15), undifferentiated SAIDs (n = 42), and polygenic SAIDs (n = 39). Notably, 38 patients were classified as rare monogenic SAIDs, linked to mutations in genes, including NLRC4, LPIN2, RIPK1, PLCG2, PIK3CD, ISG15, ZNFX1, STAT1, SOCS1, OTULIN, PTEN, GJB2, SLC29A3, and IL-17RA. Among these, consanguinity was reported in 78% of first-and second-degree relatives. Additionally, novel pathogenic or likely pathogenic variants were identified in 70% of patients with rare monogenic SAIDs, spanning 14 distinct genes.

conclusionOur cohort demonstrates that rare monogenic SAIDs and novel pathogenic variants tend to cluster within consanguineous families. These findings highlight the importance of considering consanguinity and family history in the clinical assessment of SAIDs. Larger studies involving consanguineous populations are needed to further investigate their impact on prevelance and clinical outcome. CLINICAL TRIAL NUMBER: Not applicable.