Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan.
Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
J Hum Genet. 2023 Sep;68(9):649-652. doi: 10.1038/s10038-023-01156-y. Epub 2023 May 29.
Approximately 80% of rare diseases have a genetic cause, and an accurate genetic diagnosis is necessary for disease management, prognosis prediction, and genetic counseling. Whole-exome sequencing (WES) is a cost-effective approach for exploring the genetic cause, but several cases often remain undiagnosed. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) to identify the pathogenic variants in an unsolved case using WES. RNA-seq revealed aberrant exon 4 and exon 6 splicing of ITPA. WGS showed a previously unreported splicing donor variant, c.263+1G>A, and a novel heterozygous deletion, including exon 6. Detailed examination of the breakpoint indicated the deletion caused by recombination between Alu elements in different introns. The proband was found to have developmental and epileptic encephalopathies caused by variants in the ITPA gene. The combination of WGS and RNA-seq may be effective in diagnosing conditions in proband who could not be diagnosed using WES.
大约 80%的罕见病都有遗传原因，准确的基因诊断对于疾病管理、预后预测和遗传咨询都是必要的。全外显子组测序（WES）是探索遗传原因的一种具有成本效益的方法，但仍有几个病例无法诊断。我们使用 WES 将全基因组测序（WGS）和 RNA 测序（RNA-seq）结合起来，以确定一个未解决病例的致病变异。RNA-seq 显示 ITPA 异常的外显子 4 和外显子 6 剪接。WGS 显示了一个以前未报道的剪接供体变异，c.263+1G>A，以及一个新的杂合性缺失，包括外显子 6。对断点的详细检查表明，缺失是由不同内含子中的 Alu 元件之间的重组引起的。该先证者被发现患有由 ITPA 基因变异引起的发育性和癫痫性脑病。WGS 和 RNA-seq 的结合可能对 WES 无法诊断的先证者的疾病的诊断有效。
