Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.
Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.
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DOI：
10.3389/fimmu.2023.1172004
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发表时间：
2023
影响因子：
7.3
通讯作者：
Yan, Jia
中科院分区：
文献类型：
--
作者：
Beers, Breanna J. J.;Similuk, Morgan N. N.;Ghosh, Rajarshi;Seifert, Bryce A. A.;Jamal, Leila;Kamen, Michael;Setzer, Michael R. R.;Jodarski, Colleen;Duncan, Rylee;Hunt, Devin;Mixer, Madison;Cao, Wenjia;Bi, Weimin;Veltri, Daniel;Karlins, Eric;Zhang, Lingwen;Li, Zhiwen;Oler, Andrew J. J.;Jevtich, Kathleen;Yu, Yunting;Hullfish, Haley;Bielekova, Bibiana;Frischmeyer-Guerrerio, Pamela;Dang Do, An;Huryn, Laryssa A. D. A.;Olivier, Kenneth N. N.;Su, Helen C. C.;Lyons, Jonathan J. J.;Zerbe, Christa S. S.;Rao, V. Koneti;Keller, Michael D.;Freeman, Alexandra F. F.;Holland, Steven M. M.;Franco, Luis M. M.;Walkiewicz, Magdalena A. A.;Yan, Jia
虽然拷贝数变异体（CNVs）已被认为在先天性免疫缺陷（IEI）中发挥重要作用，但这种作用的确切性质在很大程度上尚未探索。我们试图通过全基因组染色体微阵列分析（CMA）来确定CNVs在IEI儿童中的诊断作用。我们对332名不相关的儿科先证者进行了外显子组测序（ES）和CMA，以评估IEI。分析包括主要、次要和偶然发现。在332例先证者中，134例（40.4%）接受了分子诊断。其中，116/134例（86.6%）仅通过ES诊断。另外15/134例（11.2%）仅通过CMA诊断，包括两种可能的新发变化。三名（2.2%）参与者具有ES和CMA的诊断分子结果，包括两个复合杂合子和一名参与者具有两种不同的诊断。有CMA诊断贡献的参与者中有一半在至少一个非免疫基因中存在CNV，突出了这些病例的临床复杂性。总体而言，CMA促成了18/134例诊断（13.4%），使总体诊断率比单独ES提高了15.5%。ES和CMA的配对可以提供全面的评估，以澄清有助于免疫和非免疫表型的复杂因素。这种基因检测的综合方法有助于解开复杂的表型，不仅通过澄清鉴别诊断，而且在某些情况下，通过确定有助于整体临床表现的多种诊断。
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. 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. 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. 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.
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