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Origin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus

European Journal of Human Genetics (2024)Cite this article

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Abstract

Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis of pathogenic repeat expansions from ancestral premutation alleles. Our results may guide future studies in detecting novel repeat expansion disorders and elucidating repeat expansion mutational processes, thereby enhancing our understanding of human genomic variation.

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Fig. 1: Haplotype analysis of different repeat expansion configurations at the FCMTE1-SAMD12 locus.
Fig. 2: The geographic distribution of different configurations at the FCMTE1-SAMD12 locus.
Fig. 3: High-depth targeted long-read sequencing unveiled (TTTTA)exp(TTTCA)exp subreads generated by somatic variants.

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Data availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Acknowledgements

Thanks to Zhengwen Jiang and Peng Yu from Genesky Diagnostics Inc, Biobay, SIP, Suzhou, Jiangsu, China, for their help in this study. We thank Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the language of a draft of this manuscript. Finally, we are very grateful to the family members for their generous participation in this study.

Funding

This study was supported by the Medical Science and Technology Project of Zhejiang Province (2022RC030), the National Natural Science Foundation of China (NSFC) (No. 81571089, 82201393), and the Zhejiang Provincial Natural Science Foundation of China (LY23H090010, LQ24H090003).

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Author notes

  1. These authors contributed equally: Xinhui Chen, Fan Zhang, Yihua Shi.

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China

    Xinhui Chen, Fan Zhang, Yihua Shi, Haotian Wang, Dehao Yang, Lebo Wang, Jiawen Chen, Bo Wang, Zhiyuan Ouyang, Sheng Wu, Zhiru Lin, Zhidong Cen & Wei Luo

  2. Department of Neurology, Zhuji Affiliated Hospital of Wenzhou Medical University, Zhuji, China

    Miao Chen

  3. Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China

    Peng Liu

  4. Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, Zhejiang, China

    Fei Xie

  5. Wuhan Dgensee Clinical Laboratory Co., Ltd. Wuhan, Wuhan, 430075, China

    Aisi Fu

  6. Center for Tumor Precision Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430062, China

    Ben Hu

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Contributions

XC, LW, ZC contributed to the conception and design of the study; FZ, YS, HW, DY, MC, LW, PL, FX, AF, BH, BW, ZO, SW, ZL, contributed to the acquisition and analysis of data; XC, YK, JC, FZ, ZC contributed to drafting the text or preparing the figures. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Zhidong Cen or Wei Luo.

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The authors declare no competing interests.

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The ethics was approved in the Second Affiliated Hospital, Zhejiang University School of Medicine (I2019001151). Written informed consent was obtained from all participants following the Declaration of Helsinki.

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Chen, X., Zhang, F., Shi, Y. et al. Origin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01586-y

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