Exome Sequencing Uncovers Phenotypic and Genotypic Heterogeneity in 196 Indian Families Evaluated for...

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. Worldwide, and especially in India, there is a lack of systematic large cohort studies employing genomic testing early in the course of evaluation for individuals with autoinflammatory disease. Herein, we describe our experience using exome sequencing as a first-tier investigation in evaluating 202 individuals from 196 unrelated families with possible monogenic AIDs. Consanguinity was noted in 19% of the families. Recurrent fever was the most common manifestation (90%), frequently associated with arthritis (54%), skin lesions (38%), hepatosplenomegaly (23%), oral ulcers (21%) and lymphadenopathy (21%). Exome sequencing could identify a molecular diagnosis in 50 of 196 (25%) families of whom 30 (60%) had variants in genes associated with monogenic AIDs, 10 (20%) had other distinct inborn errors of immunity and 10 (20%) had monogenic conditions with phenotypic overlap with AIDs. We identified 21 variants in genes associated with monogenic AIDs, of which 20 (95%) were single nucleotide variants and one (5%) was a copy number variant. Notably, seven (33%) of the 21 variants were novel. This study highlights the diagnostic challenges posed by phenotypic overlap in this group of disorders and demonstrates the utility of exome sequencing in enabling a timely diagnosis, including conditions that mimic AIDs thereby facilitating targeted therapy and genetic counseling.