Chromosomal microarray analysis reveals copy number variants contribute to disease in children with suspected inborn errors of immunity

Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. Thus, we sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with suspected or known IEI. We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. All cases were reanalyzed following the 2022 update to the International Union of Immunological Societies (IUIS) gene list. We reviewed variants that were not in the Human Gene Mutation Database (HGMD) at the time of analysis but have since been reported in the literature. Additionally, we reviewed CNVs called using GATK-SV in 11 participants who received follow-up genome sequencing, with a focus on CNVs in new IUIS genes that could have been missed by prior CMA. Our cohort included 332 probands under 18 years old (M = 9.9 years, SD = 4.3 years) at the time of enrollment. Participants were 56.6% male. Of the 332 participants, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic findings from both ES and CMA, including two compound heterozygotes and one patient with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Reanalysis considering the 2022 IUIS gene list did not result in any new CMA diagnoses or change any existing diagnoses. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5%. Pairing ES and CMA can provide a more comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.