Laboratório de Citogenômica, Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Mendelics Análise Genômica, São Paulo, Brazil.
J Mol Diagn. 2020 Aug;22(8):1041-1049. doi: 10.1016/j.jmoldx.2020.05.007. Epub 2020 Jun 1.
Overcoming challenges for the unambiguous detection of copy number variations is essential to broaden our understanding of the role of genomic variants in the clinical phenotype. With the improvement of software and databases, whole-exome sequencing quickly can become an excellent strategy in the routine diagnosis of patients with a developmental delay and/or multiple congenital malformations. However, even after a detailed analysis of pathogenic single-nucleotide variants and indels in known disease genes, using whole-exome sequencing, some patients with suspected syndromic conditions are left without a conclusive diagnosis. These negative results could be the result of different factors including nongenetic etiologies, lack of knowledge about the genes that cause different disease phenotypes, or, in some cases, a deletion or duplication of genomic information not routinely detectable by whole-exome sequencing variant calling. Although copy number variant detection is possible using whole-exome sequencing data, such analysis presents significant challenges and cannot yet be used to replace chromosomal arrays for identification of deletions or duplications.
克服明确检测拷贝数变异的挑战对于拓宽我们对基因组变异在临床表型中的作用的理解至关重要。随着软件和数据库的改进，外显子组测序很快将成为诊断发育迟缓伴/或多发先天畸形患者的常规策略。然而，即使在详细分析了已知疾病基因中的致病性单核苷酸变异和插入缺失后，使用外显子组测序，一些疑似综合征的患者仍无法得出明确的诊断。这些阴性结果可能是由于多种因素造成的，包括非遗传病因、对导致不同疾病表型的基因的了解不足，或者在某些情况下，基因组信息的缺失或重复，而这些信息通常无法通过外显子组测序变异检测来检测到。虽然可以使用外显子组测序数据进行拷贝数变异检测，但这种分析存在很大的挑战，目前还不能替代染色体阵列来识别缺失或重复。
