Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Khleifat, Ahmad Al; Iacoangeli, Alfredo; Vugt, Joke J.F.A. van; Bowles, Harry; Moisse, Matthieu; Zwamborn, Ramona A J; Spek, Rick A. A. van der; Shatunov, Aleksey; Cooper‐Knock, Johnathan; Topp, Simon; Byrne, Ross P.; Gellera, Cinzia; López-Alonso, Victoria; Jones, Ashley; Opie-Martin, Sarah; Vural, Atay; Campos, Yolanda; Rheenen, Wouter van; Kenna, Brendan; Eijk, Kristel R. van; Kenna, Kevin P.; Weber, Markus; Smith, Bradley N.; Fogh, Isabella; Silani, Vincenzo; Morrison, Karen; Dobson, Richard; Es, Michael A. van; McLaughlin, Russell L.; Vourc’h, Patrick; Chiò, Adriano; Corcia, Philippe; Carvalho, Mamede de; Guillaume, Marc; Panades, Mónica Povedano; Mora, Jesús; Shaw, Pamela J.; Landers, John E.; Glass, Jonathan D.; Başak, Nazlı; Hardiman, Orla; Robberecht, Wim; Damme, Philip Van; Berg, Leonard H van den; Veldink, Jan H.; Al‐Chalabi, Ammar

doi:10.1038/s41525-021-00267-9

Cited by 36 publications

(30 citation statements)

References 55 publications

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“…We analyzed the carriage of NEFH alleles, taking into account the site of disease onset. Although the survival trajectories for spinal and bulbar onset patients did not differ within this cohort, it is important to include this covariate since short structural variants have previously been shown to stratify sALS patient sub-phenotype [33][34][35] . In the present study, no signi cant associations were detected between NEFH alleles and survival.…”

Section: Discussionmentioning

confidence: 97%

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset

Theunissen

Anderton

Mastaglia

et al. 2022

Preprint

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Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico SSV evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333; combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with a 2x reduced risk specifically confined to spinal-onset sALS patients in the Duke cohort (p = 0.001). Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort (p = 0.02). These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however these results need to be replicated in larger multicenter and multi-ethnic cohorts.

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Section: Discussionmentioning

confidence: 97%

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset

Theunissen

Anderton

Mastaglia

et al. 2022

Preprint

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“…The variant caller used in this study detected multiple classes of SVs, however, small inversions and insertion/deletions < 200 bp could not be analyzed by the Manta platform [27]. Further investigation into variants outside of the know ALS genes in addition to wet lab validation is required to gain a holistic understanding of the contribution of genetic variation to ALS risk and phenotype [27].…”

Section: Introductionmentioning

confidence: 94%

“…Furthermore, another recent study has investigated SVs in 6580 whole genome sequences (4315 ALS and 1880 controls) from the Project MinE cohort to determine genotype-phenotype correlations in known ALS genes. Al Khleifat, Iacoangeli [27] reported that structural variants in C9orf72 (repeat expansion), Valosin containing protein VCP (inversion) and erb-b2 receptor tyrosine kinase 4, ERBB4 (deletion) are variously associated with ALS disease risk and phenotype. The variant caller used in this study detected multiple classes of SVs, however, small inversions and insertion/deletions < 200 bp could not be analyzed by the Manta platform [27].…”

Section: Introductionmentioning

confidence: 99%

“…Al Khleifat, Iacoangeli [27] reported that structural variants in C9orf72 (repeat expansion), Valosin containing protein VCP (inversion) and erb-b2 receptor tyrosine kinase 4, ERBB4 (deletion) are variously associated with ALS disease risk and phenotype. The variant caller used in this study detected multiple classes of SVs, however, small inversions and insertion/deletions < 200 bp could not be analyzed by the Manta platform [27]. Further investigation into variants outside of the know ALS genes in addition to wet lab validation is required to gain a holistic understanding of the contribution of genetic variation to ALS risk and phenotype [27].…”

Section: Introductionmentioning

confidence: 99%

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Short structural variants as informative genetic markers for ALS disease risk and progression

Theunissen

Flynn

Anderton

et al. 2022

BMC Med

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There is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials.

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“…A recent analysis of known ALS-causing genes demonstrated a role for structural variants in this subset of genes. 6 Specifically, genomic structural variants in C9orf72 , valosin-containing protein ( VCP ) and Erb-B4 receptor tyrosine kinase 4 ( ERBB4 ) genes were shown to modify ALS risk, age, and site of onset as well as progression and survival, highlighting the role of structural variants in ALS pathogenesis. 6 Similarly, repeat expansions, which are one type of structural variation, in the C9orf72 gene as well as the medium CAG repeat in the ataxin 2 ( ATXN2 ) gene can cause ALS.…”

Section: Introductionmentioning

confidence: 99%

Identification of gene fusions associated with amyotrophic lateral sclerosis

Raghav

Dilliot

Petrozziello

et al. 2022

Preprint

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Genetics is an import risk factor for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease affecting motor neurons. Recent findings demonstrate that, in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. While such gene fusion events have been studied extensively in cancer, they have not been thoroughly investigated in ALS. We leveraged bulk RNA-Seq data from human post-mortem samples to determine whether fusion events occur in ALS. We report for the first time the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significant increase in the number of unique gene fusion in ALS compared to controls. Lastly, we have identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. Collectively, our findings reveal an enrichment of gene fusion in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

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Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Cited by 36 publications

References 55 publications

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset

Short structural variants as informative genetic markers for ALS disease risk and progression

Identification of gene fusions associated with amyotrophic lateral sclerosis

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