Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses
Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses
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DOI：
10.1038/s41436-020-0781-x
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发表时间：
2020-05-05
影响因子：
8.8
通讯作者：
Shashi, Vandana
中科院分区：
文献类型：
--
作者：
Schoch, Kelly;Tan, Queenie K. -G.;Shashi, Vandana
目的专业组织评估变异致病性的指南包括建议使用生物学相关转录本；然而，实验室在转录本选择上存在差异。方法我们描述了3例基因组结果不正确的患者，因为商业实验室没有考虑替代转录本和组织表达模式。结果在个体1中，CKDL5脑表达异构体的致病性编码变体在测序中两次被遗漏，因为该变体在分析中考虑的转录本中是内含子的。在个体2中，影响KMT2C的微缺失未在微阵列上报道，因为该基因的近端外显子缺失在健康个体中可见；然而，这名患者的远端缺失涉及脑表达的KMT2C亚型，因此诊断为Kleefstra综合征。据报道，个体3在外显子组OFD1的第10外显子上具有致病性变异，但没有OFD1相关疾病的典型特征。由于外显子10是由生物学上更相关的OFD1转录本剪接而来，因此确定他没有OFD1疾病。这些例子说明了当遗传结果为阴性或与表型不一致时，考虑替代转录本作为潜在混杂因素的重要性。
Purpose Guidelines by professional organizations for assessing variant pathogenicity include the recommendation to utilize biologically relevant transcripts; however, there is variability in transcript selection by laboratories. Methods We describe three patients whose genomic results were incorrect, because alternative transcripts and tissue expression patterns were not considered by the commercial laboratories. Results In individual 1, a pathogenic coding variant in a brain-expressed isoform of CKDL5 was missed twice on sequencing, because the variant was intronic in the transcripts considered in analysis. In individual 2, a microdeletion affecting KMT2C was not reported on microarray, since deletions of proximal exons in this gene are seen in healthy individuals; however, this individual had a more distal deletion involving the brain-expressed KMT2C isoform, giving her a diagnosis of Kleefstra syndrome. Individual 3 was reported to have a pathogenic variant in exon 10 of OFD1 on exome, but had no typical features of the OFD1-related disorders. Since exon 10 is spliced from the more biologically relevant transcripts of OFD1, it was determined that he did not have an OFD1 disorder. Conclusion These examples illustrate the importance of considering alternative transcripts as a potential confounder when genetic results are negative or discordant with the phenotype.