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

Zeng, Sheng; Zhang, Mei-yun; Wang, Xuejing; Hu, Zhengmao; Li, Jin‐chen; Li, Nan; Wang, Junling; Liang, Fan; Yang, Qi; Liu, Qian; Li, Fang; Hao, Junwei; Shi, Fu‐Dong; Ding, Xin; Teng, Jie; Yin, Xiaomeng; Jiang, Hong; Liao, Wei‐Ping; Liu, Jingyu; Wang, Kai; Xia, Kun; Tang, Beisha

doi:10.1136/jmedgenet-2018-105484

Cited by 80 publications

(69 citation statements)

References 22 publications

(20 reference statements)

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“…For example, expansion of (CAG) n repeats in 13 different genes causes SCAs. Similarly, recently discovered expansions of (TTTTA) n (TTTCA) m repeats in the introns of five different genes are all linked to FAME (32,(67)(68)(69). Therefore, researchers have proposed toxic gain-offunction mechanisms, which could be either at the RNA or protein levels.…”

Section: From Expanded Dna Repeats To Diseasementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

188

178

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Section: From Expanded Dna Repeats To Diseasementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

188

178

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“…Another benefit of Phen2Gene is that it is variant agnostic. Structural variants and repeat expansions in intronic regions are known to cause disease 105,106 , and on average, there are more than 20,000 structural variants (SVs) in the human genome 107 . Based on our calculation using the gold standard SV call set from HG002 108 and the gene annotation file from GENCODE (v25), more than half of the structural variants overlap with genes and most overlap intronic regions.…”

Section: Discussionmentioning

confidence: 99%

Phen2Gene: Rapid Phenotype-Driven Gene Prioritization for Rare Diseases

Zhao

Havrilla

et al. 2019

Preprint

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Human Phenotype Ontology (HPO) terms are increasingly used in diagnostic settings to aid in the characterization of patient phenotypes. The HPO annotation database is updated frequently and can provide detailed phenotype knowledge on various human diseases, and many HPO terms are now mapped to candidate causal genes with binary relationships. To further improve the genetic diagnosis of rare diseases, we incorporated these HPO annotations, gene-disease databases, and gene-gene databases in a probabilistic model to build a novel HPO-driven gene prioritization tool, Phen2Gene. Phen2Gene accesses a database built upon this information called the HPO2Gene Knowledgebase (H2GKB), which provides weighted and ranked gene lists for every HPO term. Phen2Gene is then able to access the H2GKB for patient-specific lists of HPO terms or PhenoPackets descriptions supported by GA4GH

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“…Whole‐genome long‐read sequencing has been utilized to investigate the structure of the (TTTCA) n insertion and the accompanying (TTTTA) n expansion in SAMD12 . However, the accurate structure has not been able to be identified because of the very common insertion and deletion (indel) errors in long‐read sequencing, and the very limited reads (only two to four) spanning the repeat expansion region . To tackle this issue, we performed targeted long‐read sequencing using LR‐PCR products from 2 patients and 1 asymptomatic carrier in this study.…”

Section: Discussionmentioning

confidence: 99%

“…14,16,17 However, the accurate structure has not been able to be identified because of the very common insertion and deletion (indel) errors in long-read sequencing, and the very limited reads (only two to four) spanning the repeat expansion region. 14,16,17 To tackle this issue, we performed targeted long-read sequencing using LR-PCR products from 2 patients and 1 asymptomatic carrier in this study. This targeted long-read sequencing approach enabled us to reveal the accurate structures of the expanded repeats and gain a better understanding of the repeat expansions in FCMTE1.…”

Section: Discussionmentioning

confidence: 99%

“…Second, 70% to 90% (TTTTA) n repeats and 73% to 91% (TTTCA) n repeats were previously reported from whole-genome long-read sequencing in a limited number of long reads spanning the repeat expansion region. 14,16 It is hard to identify whether the other 9% to 30% repeat motifs (such as TTTTG, TTTA, TTTTTA, and TTTG) in these reads were interruptions that might influence the phenotype or single-nucleotide and indel errors. 18 In our targeted long-read sequencing, the expanded repeat motifs, (TTTTA) n , (TTTCA) n , and (TTTGA) n , were all identified as close to 100% pure (Supporting Information Figs.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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

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Long-read sequencing identified intronic repeat expansions inSAMD12from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy

Cited by 80 publications

References 22 publications

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Phen2Gene: Rapid Phenotype-Driven Gene Prioritization for Rare Diseases

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

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Long-read sequencing identified intronic repeat expansions inSAMD12from Chinese pedigrees affected with familial cortical myoclonic tremor with epilepsy

Cited by 80 publications

References 22 publications

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Phen2Gene: Rapid Phenotype-Driven Gene Prioritization for Rare Diseases

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

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