Van Deynze Kinsey, Mumm Camille, Maltby Connor J, Switzenberg Jessica A, Todd Peter K, Boyle Alan P
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Nucleic Acids Res. 2025 Jan 11;53(2). doi: 10.1093/nar/gkae1202.
Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization of disease-associated repeat loci remains resource intensive and often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel and HMMSTR, a sequence-based tandem repeat copy number caller which outperforms current signal- and sequence-based callers relative to two assemblies and we show it performs with high accuracy in heterozygous regions and at low read coverage. The flexible panel allows us to capture disease associated regions at an average coverage of >150x. Using these tools, we successfully characterize known or suspected repeat expansions in patient derived samples. In these samples, we also identify unexpected expanded alleles at tandem repeat loci not previously associated with the underlying diagnosis. This genotyping approach for tandem repeat expansions is scalable, simple, flexible and accurate, offering significant potential for diagnostic applications and investigation of expansion co-occurrence in neurodegenerative disorders.
串联重复序列约占人类基因组的8%，并与50多种神经退行性疾病相关。对疾病相关重复基因座进行准确表征仍然需要大量资源，而且往往缺乏高分辨率的基因型分型。我们推出了一种多重靶向纳米孔测序面板和HMMSTR，这是一种基于序列的串联重复拷贝数分型工具，相对于两个基因组组装，它的性能优于当前基于信号和序列的分型工具，并且我们表明它在杂合区域和低读数覆盖率下具有高精度。灵活的面板使我们能够以平均>150倍的覆盖率捕获疾病相关区域。使用这些工具，我们成功地表征了患者来源样本中已知或疑似的重复序列扩增。在这些样本中，我们还在以前与潜在诊断无关的串联重复基因座上鉴定出意外的扩增等位基因。这种用于串联重复序列扩增的基因分型方法具有可扩展性、简单性、灵活性和准确性，在神经退行性疾病的诊断应用和扩增共现研究方面具有巨大潜力。
