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Mov Disord. 2019 Sep 4. doi: 10.1002/mds.27832. [Epub ahead of print]

Intronic (TTTGA)n insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy.

Cen Z1,2, Chen Y1,2, Yang D1,2, Zhu Q3, Chen S1,2, Chen X1, Wang B1, Xie F1,4, Ouyang Z1, Jiang Z5, Fu A6, Hu B6, Yin H1, Qiu X1, Yu F5, Du X7,8, Hao W8, Liu Y9, Wang H1,2, Wang L1, Yu X10, Xiao Y3, Liu C11, Xiao J12, Zhou Y13, Yang W10, Zhang B1, Luo W1.

Author information

1
Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
2
Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
3
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
4
Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
5
Genesky Diagnostics Inc, Biobay, SIP, Suzhou, Jiangsu, China.
6
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, China.
7
Epilepsy Center, Department of Neurosurgery, Humanity Hospital, Xiamen, Fujian, China.
8
Department of Neurology, West District, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
9
Institute of Epilepsy, Shanxi Medical University, Taiyuan, Shanxi, China.
10
Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
11
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York, USA.
12
Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
13
Department of Neurology, MedStar St Mary's Hospital/Georgetown University Hospital, MedStar Medical Group, Leonardtown, Maryland, USA.

Abstract

BACKGROUND:

Intronic (TTTCA)n insertions in the SAMD12, TNRC6A, and RAPGEF2 genes have been identified as causes of familial cortical myoclonic tremor with epilepsy.

OBJECTIVE:

To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)n insertions in SAMD12, TNRC6A, and RAPGEF2.

METHODS:

Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)n insertion. Targeted long-read sequencing was performed to confirm the accurate structure of the (TTTGA)n insertion.

RESULTS:

We identified a novel expanded intronic (TTTGA)n insertion at the same site as the previously reported (TTTCA)n insertion in SAMD12. This insertion cosegregated with familial cortical myoclonic tremor with epilepsy in 1 Chinese pedigree with no (TTTCA)n insertion. In the targeted long-read sequencing of 2 patients and 1 asymptomatic carrier in this pedigree, with 1 previously reported (TTTCA)n -insertion-carrying patient as a positive control, a respective total of 302, 159, 207, and 50 on-target subreads (predicated accuracy: ≥90%) spanning the target repeat expansion region were generated. These sequencing data revealed the accurate repeat expansion structures as (TTTTA)114-123 (TTTGA)108-116 in the pedigree and (TTTTA)38 (TTTCA)479 in (TTTCA)n -insertion-carrying patient.

CONCLUSION:

The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)n and (TTTCA)n insertions. Our finding offers a novel possible cause for familial cortical myoclonic tremor with epilepsy and might shed light on the identification of genetic causes of this disease in pedigrees with no detected (TTTCA)n insertion in the reported causative genes. © 2019 International Parkinson and Movement Disorder Society.

KEYWORDS:

(TTTGA)n insertion; SAMD12; familial cortical myoclonic tremor with epilepsy; long-read sequencing

PMID:
31483537
DOI:
10.1002/mds.27832

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