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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Data availability
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
References
Cen Z, Jiang Z, Chen Y, Zheng X, Xie F, Yang X, et al. Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. Brain. 2018;141:2280–8.
Ishiura H, Doi K, Mitsui J, Yoshimura J, Matsukawa MK, Fujiyama A, et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018;50:581–90.
van den Ende T, Sharifi S, van der Salm SMA, van Rootselaar AF. Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review. Tremor Other Hyperkinet Mov. 2018;8:503.
Corbett MA, Kroes T, Veneziano L, Bennett MF, Florian R, Schneider AL, et al. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat Commun. 2019;10:4920.
Florian RT, Kraft F, Leitão E, Kaya S, Klebe S, Magnin E, et al. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nat Commun. 2019;10:4919.
Yeetong P, Pongpanich M, Srichomthong C, Assawapitaksakul A, Shotelersuk V, Tantirukdham N, et al. TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4. Brain. 2019;142:3360–6.
Yeetong P, Dembélé ME, Pongpanich M, Cissé L, Srichomthong C, Maiga AB, et al. Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8. Mov Disord. 2024;39:164–72.
Bennett MF, Oliver KL, Regan BM, Bellows ST, Schneider AL, Rafehi H, et al. Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families. Eur J Hum Genet. 2020;28:973–8.
Yeetong P, Chunharas C, Pongpanich M, Bennett MF, Srichomthong C, Pasutharnchat N, et al. Founder effect of the TTTCA repeat insertions in SAMD12 causing BAFME1. Eur J Hum Genet. 2021;29:343–8.
Mizuguchi T, Toyota T, Miyatake S, Mitsuhashi S, Doi H, Kudo Y, et al. Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment. Brain. 2021;144:1103–17.
Cen Z, Chen Y, Yang D, Zhu Q, Chen S, Chen X, et al. Intronic (TTTGA)(n) insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy. Mov Disord. 2019;34:1571–6.
Gandolfo LC, Bahlo M, Speed TP. Dating rare mutations from small samples with dense marker data. Genetics. 2014;197:1315–27.
Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85:544–57.
Loureiro JR, Oliveira CL, Mota C, Castro AF, Costa C, Loureiro JL, et al. Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution. Hum Mutat. 2019;40:404–12.
Depienne C, Mandel JL. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges? Am J Hum Genet. 2021;108:764–85.
Rubinsztein DC, Leggo J, Goodburn S, Barton DE, Ferguson-Smith MA. Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington’s disease (HD) gene provides an explanation for an apparent ‘founder’ HD haplotype. Hum Mol Genet. 1995;4:203–6.
Landrian I, McFarland KN, Liu J, Mulligan CJ, Rasmussen A, Ashizawa T. Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type 10 (SCA10) expansions. PLoS One. 2017;12:e0175958.
Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51:649–58.
Dominik N, Magri S, Currò R, Abati E, Facchini S, Corbetta M, et al. Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis. Brain. 2023;146:5060–9.
Stevanovski I, Chintalaphani SR, Gamaarachchi H, Ferguson JM, Pineda SS, Scriba CK, et al. Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing. Sci Adv. 2022;8:eabm5386.
Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, et al. Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4. Mov Disord. Published online January 10, 2024.
Pascarella G, Hon CC, Hashimoto K, Busch A, Luginbuhl J, Parr C, et al. Recombination of repeat elements generates somatic complexity in human genomes. Cell. 2022;185:3025–40.e6.
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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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.
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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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DOI: https://doi.org/10.1038/s41431-024-01586-y