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Sarah Silverstein¹, Thomas Cassini², Jiayu Fu³

¹Neuromuscular and Neurogenetics Disorder of Childhood Section, NINDS, NIH, Bethesda, MD, United States of America; Undiagnosed Disease Program, NHGRI, NIH, Bethesda, MD, United States of America.

Molecular genetics and metabolism

|April 11, 2025

概括

当基因组测序失败时,RNA测序有助于诊断罕见疾病. 在一个发育迟缓的患者中,RNA测序发现了新的NBAS基因变异,扩大了已知的NBAS缺陷谱.

科学领域:

遗传学和基因组学遗传学和基因组学
罕见疾病罕见疾病
分子生物学分子生物学

背景情况:

罕见疾病影响10人中的1人,这给诊断带来了挑战.
整体外体和基因组测序实现~30%的诊断率.
RNA测序 (RNAseq) 可以补充基因组分析,以改善诊断.

研究的目的:

研究RNA测序在诊断具有复杂表型和非诊断性基因组测序的患者中的实用性.
为了确定一个年轻女子严重多系统性疾病的遗传原因.
扩大对NBAS基因相关疾病的理解.

主要方法:

在患者的皮肤纤维细胞上进行RNA测序.
分析了RNA测序数据,包括对二进制对齐图 (BAM) 文件的手动检查.
在NBAS基因中识别和特征化复合异质合体变异体.
评估了已识别的变异对基因表达和蛋白质功能的预测影响.

主要成果:

与对照组相比,RNA测序显示患者的NBAS基因表达显著减少.
发现了两种罕见的NBAS变体:一种深层内基拼接变体,产生伪exon (NM_015909.4:c.2423+403G>C) 和一种过早终止的代变体 (NM_015909.4:c.4753C>T; p.Arg1585Ter).
预计这两种变体都会导致无意中介衰变,导致NBAS功能丧失.
该患者呈现出严重的表型,与之前报告的NBAS缺陷病例不同.

结论:

RNA测序是识别诊断候选人的一个有价值的工具,在非诊断基因组测序的情况下.
在NBAS中识别的化合物异构变异扩大了NBAS缺陷的基因型和表型谱.
这一案例凸显了将RNA测序集成为罕见疾病综合性遗传诊断的重要性.

关键词:

临床诊断临床诊断临床诊断遗传学是一个遗传学.代谢遗传学代谢遗传学有关RNA测序的RNA测序罕见疾病是一种罕见的疾病.

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