AUTHOR=Beers Breanna J. , Similuk Morgan N. , Ghosh Rajarshi , Seifert Bryce A. , Jamal Leila , Kamen Michael , Setzer Michael R. , Jodarski Colleen , Duncan Rylee , Hunt Devin , Mixer Madison , Cao Wenjia , Bi Weimin , Veltri Daniel , Karlins Eric , Zhang Lingwen , Li Zhiwen , Oler Andrew J. , Jevtich Kathleen , Yu Yunting , Hullfish Haley , Bielekova Bibiana , Frischmeyer-Guerrerio Pamela , Dang Do An , Huryn Laryssa A. , Olivier Kenneth N. , Su Helen C. , Lyons Jonathan J. , Zerbe Christa S. , Rao V. Koneti , Keller Michael D. , Freeman Alexandra F. , Holland Steven M. , Franco Luis M. , Walkiewicz Magdalena A. , Yan Jia TITLE=Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1172004 DOI=10.3389/fimmu.2023.1172004 ISSN=1664-3224 ABSTRACT=Purpose

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. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.

Methods

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.

Results

Of the 332 probands, 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 molecular findings from both ES and CMA, including two compound heterozygotes and one participant 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. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.

Conclusion

Pairing ES and CMA can provide a 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.