Exome sequencing uncovers phenotypic and genotypic heterogeneity in 198 Indian families evaluated for autoinflammatory disorders

Autoinflammatory disorders (AIDs) are a clinically heterogeneous group of inborn errors of immunity primarily caused by dysregulation in the innate immune system. Clinical diagnosis is often challenging due to clinical heterogeneity and the overlapping phenotypes with other inborn errors of immunity and monogenic conditions that mimic AIDs. We describe the phenotypic and genotypic findings in 204 individuals from 198 unrelated families with clinical manifestations suggestive of monogenic AIDs. Recurrent fever was the most common manifestation (89%), frequently associated with arthritis (53%), skin lesions (37%), hepatosplenomegaly (23%), oral ulcers (21%) and lymphadenopathy (20%). A molecular diagnosis was achieved in 61 of 198 (31%) families. Of these, 34 (56%) families had variants in genes associated with monogenic AIDs, 15 (26%) families with other distinct inborn errors of immunity and 12 (18%) families had monogenic conditions resembling AIDs. Whole exome sequencing identified 49 (98%) single nucleotide variants and one (2%) copy number variant, causing 35 monogenic disorders. Notably, 24 (48%) of the variants were novel. This study highlights the diagnostic challenges posed by phenotypic overlap and demonstrates the utility of exome sequencing in clinical practice, enabling timely diagnosis, improved patient management and genetic counseling.