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

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

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

“…59 However, other pathogenic motifs than ATTTC repeats could exist, as suggested by the identification of SAMD12 expansions composed of ATTTG instead of ATTTC repeats in a large Chinese family affected by FAME. 105 SAMD12 expansions have been reported mainly in families from Japan, China, India, and Sri Lanka, 49,106 while STARD7 and MARCHF6 expansions seem to be restricted to families from European ancestry. 58,59 This geographical distribution results from ancient founder effects originating from Asia or Europe, respectively, and may be useful for initial genetic testing prioritization.…”

Comprehensive genetic, clinical and electrophysiological studies of familial cortical myoclonic tremor with epilepsy 1 highlight the role of gene configurations

“…Since the identification of the causative mutation in FCMTE1 in 2018, a rapidly increasing number of SAMD12-related FCMTE1 pedigrees have been reported. [13,14,20] In this study, we investigated the TTTTA/TTTCA expansion mutation in 76 patients from 20 Chinese FCMTE1 pedigrees. By RP-PCR and nanopore sequencing, we identified two types of TTTTA/TTTCA expansion patterns, (TTTTA) exp (TTTCA) exp and (TTTTA) exp (TTTCA) exp (TTTTA) exp , the latter of which contained much lower copy numbers but presented with more severe symptoms.…”

“…One Chinese pedigree also displayed (TTTTA) exp (TTTGA) exp in SAMD12. [14] In FCMTE1 pedigrees without SAMD12 mutations, repeats were identified in TNRC6A (16p21.1) and RAPGEF2 (4q32.2). [13] Patients carrying these mutations usually manifest tremor-like myoclonus and generalized tonic and clonic seizures (GTCSs).…”

Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and SAMD12 intronic repeat expansion

“…Thus, the exact mechanism of FCMTE with intronic repeat expansions in SAMD12 is not known. Identification of expanded intronic pentanucleotide repeats in five unrelated genes: SAMD12 , 9,10,12,13,27 TNRC6A , 9 RAPGEF2 , 9 STARD7 , 25 and MARCH6 26 as the underlying cause of FCMTE in multiple ethnicities suggests that the expanded repeats themselves are pathogenic. Interestingly, more than thirty neurological, neurodegenerative, and neuromuscular diseases are known to be caused by expansions of coding or noncoding repeats 28–31 .…”