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. 2023 May 5:14:1172004.
doi: 10.3389/fimmu.2023.1172004. eCollection 2023.

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity

Breanna J Beers  1 , Morgan N Similuk  1 , Rajarshi Ghosh  1 , Bryce A Seifert  1 , Leila Jamal  2 , Michael Kamen  1 , Michael R Setzer  1 , Colleen Jodarski  1 , Rylee Duncan  1 , Devin Hunt  1 , Madison Mixer  1 , Wenjia Cao  1 , Weimin Bi  3   4 , Daniel Veltri  1 , Eric Karlins  1 , Lingwen Zhang  1 , Zhiwen Li  1 , Andrew J Oler  1 , Kathleen Jevtich  1 , Yunting Yu  1 , Haley Hullfish  1 , Bibiana Bielekova  1 , Pamela Frischmeyer-Guerrerio  1 , An Dang Do  5 , Laryssa A Huryn  6 , Kenneth N Olivier  7 , Helen C Su  1 , Jonathan J Lyons  1 , Christa S Zerbe  1 , V Koneti Rao  1 , Michael D Keller  1 , Alexandra F Freeman  1 , Steven M Holland  1 , Luis M Franco  8 , Magdalena A Walkiewicz  1 , Jia Yan  1
Affiliations

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity

Breanna J Beers et al. Front Immunol. .

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.

Trial registration: ClinicalTrials.gov NCT03206099.

Keywords: copy number; diagnosis; genetic; immunity; microarray; pediatric; primary immunodeficiency; sequencing.

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Conflict of interest statement

WB is an employee of Baylor Genetics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer IC declared a shared affiliation, with no collaboration, with one of the authors, WB, to the handling editor at the time of the review.

Figures

Figure 1
Figure 1
Genetic ancestry. We generated genomic ancestry principal components from germline variation using peddy version 0.4.6 (39) and the 1000 Genomes phase 3 reference panel of 2,504 individuals (40).
Figure 2
Figure 2
(A) Distribution of CMA results. Normal CMAs included all tests that did not find evidence of CNVs meeting the performing laboratory’s reporting guidelines. Non-diagnostic abnormal CMAs included CNVs of unclear clinical significance, findings of carrier status only, and changes in non-disease associated regions. Importantly, of the 18 diagnostic CNVs, only half included genes listed by the IUIS as a cause of IEI at the time of analysis. (B) Source of molecular diagnoses. Although most participants were diagnosed by ES alone, CMA accounted for a significant increase in diagnostic yield. Most participants with diagnostic CNVs had inconclusive ES results.
Figure 3
Figure 3
Size, type, and region of interest in diagnostic CNVs. CNVs ranged in size from 1.08 kb to 70.786 Mb, with a median of 0.493 Mb. Notably, four out of the five copy number gains in our cohort were linked to neurological phenotypes.
See this image and copyright information in PMC

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