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

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. (c) 2019 International Parkinson and Movement Disorder Society