The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-12-05 DOI:10.1002/mds.30077

Zhongbo Chen MRCP, PhD, Pilar Alvarez Jerez MSc, Claire Anderson PhD, Martin Paucar MD, PhD, Jasmaine Lee MSc, Daniel Nilsson PhD, Hannah Macpherson MSc, Annarita Scardamaglia BSc, Kylie Montgomery BSc, John Hardy FMedSci, PhD, Andrew B. Singleton PhD, Arianna Tucci MD, PhD, Katherine D. Mathews MD, PhD, Ying-Hui Fu PhD, Martin Engvall MD, PhD, José Laffita-Mesa MD, PhD, Inger Nennesmo MD, PhD, Anna Wedell MD, PhD, Louis J. Ptáček MD, PhD, Cornelis Blauwendraat PhD, Emil K. Gustavsson PhD, Per Svenningsson MD, PhD, Mina Ryten MD, PhD, Henry Houlden MD, PhD

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Abstract

Background

The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders.

Methods

Given that the pathogenic repeat expansion is rare on a population level, we proposed a common ancestor across all families. Here, we employed targeted long-read sequencing through adaptive sampling, enriching for the chr16q22 region of interest.

Results

Using phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion.

Conclusion

This study provides further insight into the genetic architecture of SCA4. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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脊髓小脑性共济失调4型的ZFHX3 GGC重复扩增具有共同的祖先始祖

在脊髓小脑性共济失调4型（SCA4）的ZFHX3中发现杂合外显子GGC重复扩增，解决了长达25年的诊断难题。我们使用适应性长读测序来破译犹他州家族和来自爱荷华州瑞典血统的不相关家族的致病扩展。与我们的发现同时，其他研究小组在犹他州、瑞典和德国的受影响个体中发现了相同的重复扩增，这突出了当前检测新型重复扩增疾病的关键时刻。方法考虑到致病性重复扩增在种群水平上是罕见的，我们提出了所有家庭的共同祖先。在这里，我们通过自适应采样采用了靶向长读测序，富集了感兴趣的chr16q22区域。结果利用来自犹他州、爱荷华州和瑞典南部的个体的分阶段测序结果，我们确认了一个共同的~2000年前的祖先单倍型，其中包含重复扩增。结论本研究进一步揭示了SCA4的遗传结构。©2024作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.