Background 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.
Methods 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.
Results 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.
Conclusions 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
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KW, KX and B-sT contributed equally.
Contributors SZ performed the research, analysed the data and wrote the paper. M-yZ, J-wH, F-dS, X-jW, X-bD, J-fT, NL and X-mY provided the samples and assisted in clinical follow-up. Z-mH, J-cL, J-lW, FL, QY, QL and LF assisted in bioinformatics analysis. HJ, W-pL and J-yL supervised the study. KW, KX and B-sT designed the research, and provided financial and administrative support.
Funding This work was supported by the Program of National Natural Science Foundation of China (#81130021, #81430023 and #81300980).
Competing interests FL and QY are employees and KW is consultant of GrandOmics Biosciences.
Patient consent Obtained.
Ethics approval The study was approved by the Ethical Committee of Xiangya Hospital of Central South University in China (equivalent to an institutional review board).
Provenance and peer review Not commissioned; externally peer reviewed.