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J Med Genet. 2019 Apr;56(4):265-270. doi: 10.1136/jmedgenet-2018-105484. Epub 2018 Sep 7.

Long-read sequencing identified intronic repeat expansions in SAMD12 from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy.

Zeng S1, Zhang MY2, Wang XJ3,4, Hu ZM5, Li JC5,6, Li N1, Wang JL1,5,7, Liang F8, Yang Q8, Liu Q9,10, Fang L9,10, Hao JW11, Shi FD11, Ding XB3,4, Teng JF3,4, Yin XM1,4, Jiang H1,5,6,7, Liao WP12, Liu JY13, Wang K#9,10, Xia K#5, Tang BS#1,5,6,7,14,15,16.

Author information

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurology, Tianjin Union Medical Center, Tianjin, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, Hunan, China.
Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan, China.
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China.
GrandOmics Biosciences, Beijing, China.
Raymond G Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Neurology, General Hospital, Tianjin Medical University, Tianjin, China.
Institute of Neuroscience, Department of Neurology of The Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Parkinson's Disease Center of Beijing Institute for Brain Disorders, Beijing, China.
Collaborative Innovation Center for Brain Science and China, Shanghai, China.
Collaborative Innovation Center for Genetics and Development, Shanghai, China.
Contributed equally



The locus for familial cortical myoclonic tremor with epilepsy (FCMTE) has long been mapped to 8q24 in linkage studies, but the causative mutations remain unclear. Recently, expansions of intronic TTTCA and TTTTA repeat motifs within SAMD12 were found to be involved in the pathogenesis of FCMTE in Japanese pedigrees. We aim to identify the causative mutations of FCMTE in Chinese pedigrees.


We performed genetic linkage analysis by microsatellite markers in a five-generation Chinese pedigree with 55 members. We also used array-comparative genomic hybridisation (CGH) and next-generation sequencing (NGS) technologies (whole-exome sequencing, capture region deep sequencing and whole-genome sequencing) to identify the causative mutations in the disease locus. Recently, we used low-coverage (~10×) long-read genome sequencing (LRS) on the PacBio Sequel and Oxford Nanopore platforms to identify the causative mutations, and used repeat-primed PCR for validation of the repeat expansions.


Linkage analysis mapped the disease locus to 8q23.3-24.23. Array-CGH and NGS failed to identify causative mutations in this locus. LRS identified the intronic TTTCA and TTTTA repeat expansions in SAMD12 as the causative mutations, thus corroborating the recently published results in Japanese pedigrees.


We identified the pentanucleotide repeat expansion in SAMD12 as the causative mutation in Chinese FCMTE pedigrees. Our study also suggested that LRS is an effective tool for molecular diagnosis of genetic disorders, especially for neurological diseases that cannot be positively diagnosed by conventional clinical microarray and NGS technologies.


familial cortical myoclonic tremor with epilepsy; long read sequencing; repeat expansion; samd12

Conflict of interest statement

Competing interests: FL and QY are employees and KW is consultant of GrandOmics Biosciences.

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