Repeat Expansion Disorders: Mechanisms and Therapeutics

Ellerby, Lisa M.

doi:10.1007/s13311-019-00823-3

Cited by 28 publications

(23 citation statements)

References 32 publications

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“…DRPLA is considered to be the third most common autosomal dominant ataxia in the Japanese population, accounting for approximately 7.3-20% of autosomal dominant SCA [54,87,91]. Whilst it is believed to be rare in non-Asian populations, there are no accurate reports on the worldwide prevalence of DRPLA, [13,25,44,55,60,68,94]. b Clinical features-The primary clinical features of DRPLA are ataxia and cognitive impairment, however, the age of onset affects the clinical presentation, with different symptoms observed between adult-onset and juvenile-onset DRPLA (Wardle et al [98]; [34,48,55].…”

Section: Global Burdenmentioning

confidence: 99%

“…≥ 20 repeats are considered normal mutable alleles that expand on transmission and result in symptoms in the next generation, and ≥ 48 repeats demonstrate fully penetrant clinical phenotype. The unstable CAG repeat sequence causes a polyglutamine (polyQ) expansion in the atrophin-1 protein [ 13 , 25 , 44 , 55 , 60 , 68 , 94 ]. b Clinical features —The primary clinical features of DRPLA are ataxia and cognitive impairment, however, the age of onset affects the clinical presentation, with different symptoms observed between adult-onset and juvenile-onset DRPLA (Wardle et al [ 98 ]; [ 34 , 48 , 55 ].…”

Section: Current Understanding Of Drplamentioning

confidence: 99%

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DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

Chaudhry

Anthanasiou-Fragkouli

Houlden

2020

J Neurol

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Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder caused by CAG repeat expansions in the atrophin-1 gene and is inherited in an autosomal dominant fashion. There are currently no disease-modifying treatments available. The broad development of therapies for DRPLA, as well as other similar rare diseases, has hit a roadblock due to the rarity of the condition and the wide global distribution of patients and families, consequently inhibiting biomarker development and therapeutic research. Considering the shifting focus towards diverse populations, widespread genetic testing, rapid advancements in the development of clinical and wet biomarkers for Huntington’s disease (HD), and the ongoing clinical trials for antisense oligonucleotide (ASO) therapies, the prospect of developing effective treatments in rare disorders has completely changed. The awareness of the HD ASO program has prompted global collaboration for rare disorders in natural history studies and the development of biomarkers, with the eventual goal of undergoing treatment trials. Here, we discuss DRPLA, which shares similarities with HD, and how in this and other repeat expansion disorders, neurogenetics groups like ours at UCL are gearing up for forthcoming natural history studies to accelerate future ASO treatment trials to hopefully emulate the progress seen in HD.

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Section: Global Burdenmentioning

confidence: 99%

Section: Current Understanding Of Drplamentioning

confidence: 99%

DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

Chaudhry

Anthanasiou-Fragkouli

Houlden

2020

J Neurol

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“…In the era of emerging therapies for these disorders early detection may become crucial. 22 As a result this is now being considered for adoption in the NHS England National Genomic Test Directory for application to undiagnosed rare neurologic disease in direct healthcare.…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing for diagnosis of neurological repeat expansion disorders

Ibáñez

Polke²,

Hagelstrom

et al. 2020

Preprint

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Background: Repeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach. Methods: WGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders. Findings: WGS RE detection showed minimum 97.3% sensitivity and 99.6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate. Interpretation: We show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.

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“…We examine the utility of long-read sequencing when studying mtDNA and consider its potential application in deciphering unresolved nDNA causes of PMD, including SVs, short tandem repeat variants, and epigenetic changes, none of which have yet been established as causes of PMD but are increasingly recognized as causative in other neurogenetic conditions 36 . Finally, we discuss the use of NGS-based transcriptomics (RNA-seq) in identifying pathogenic variants and helping confirm causality, including for mitochondrial tRNA (mt-tRNA)-related disorders.…”

Section: [H1] Approaches To Molecular Diagnosismentioning

confidence: 99%

Applying genomic and transcriptomic advances to mitochondrial medicine

et al. 2021

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Next generation sequencing (NGS) has increased our understanding of the molecular basis of many primary mitochondrial diseases (PMDs). Despite this progress, many patients with suspected PMD remain without a genetic diagnosis, which limits their access to in-depth genetic counselling, reproductive options and clinical trials, in addition to hampering our efforts to understand the underlying disease mechanisms. Although a considerable improvement over their predecessors, current methods for sequencing the mitochondrial and nuclear genomes have important limitations, and molecular diagnostic techniques are often manual and time consuming. However, recent advances offer realistic solutions to these challenges. In this Review, we discuss the current genetic testing approach for PMDs and the opportunities that exist for increased use of whole-genome NGS of nuclear and mitochondrial DNA (mtDNA) in the clinical environment. We consider the possible role for long-read approaches in sequencing of mtDNA and in the identification of novel nuclear genomic causes of PMDs. We examine the expanding applications of RNA sequencing, including the detection of cryptic variants that affect splicing and gene expression, as well as the interpretation of rare and novel mitochondrial transfer RNA variants.

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Repeat Expansion Disorders: Mechanisms and Therapeutics

Cited by 28 publications

References 32 publications

DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder

Whole genome sequencing for diagnosis of neurological repeat expansion disorders

Applying genomic and transcriptomic advances to mitochondrial medicine

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