An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics.

Publication date: May 25, 2021

Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington’s disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic ‘AAGGG’ repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of ‘CGG’ repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e. g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion. We anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.

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Concepts Keywords
Dementia Genotype
Diagnostics Cerebellum
Myotonic Ataxia
Neurological Autosomal dominant disorders
Notch2nlc Rare diseases
Pcr Neurological disorders
Sclerosis Microsatellite
RFC1
Branches of biology
Unsolved diseases
Important neurological disease
Tandemrepeat expansion disorders

Semantics

Type Source Name
disease MESH congenital central hypoventilation syndrome
disease MESH blepharophimosis
disease MESH uncertainty
disease MESH hypotonia
disease MESH myotonia
disease MESH cataracts
disease MESH intellectual disability
disease MESH Unverricht Lundborg disease
pathway KEGG Spinocerebellar ataxia
disease MESH spinocerebellar ataxia
disease MESH muscular atrophy
disease MESH leukoencephalopathy
disease MESH oculopharyngeal muscular dystrophy
disease MESH oculopharyngodistal myopathy
disease MESH FXTAS fragile x tremor ataxia syndrome
disease MESH early infantile epileptic encephalopathy
disease MESH dentatorubral pallidoluysian atrophy
disease MESH epilepsy
pathway KEGG Huntington disease
disease MESH Huntington disease
disease MESH myopathy
disease MESH tremor
disease MESH myoclonic epilepsy
disease MESH X linked lissencephaly
disease MESH dementia
disease MESH frameshift mutations
drug DRUGBANK L-Alanine
disease MESH ataxias
disease MESH death
drug DRUGBANK Amino acids
drug DRUGBANK L-Glutamine
drug DRUGBANK Ranitidine
disease MESH development
disease MESH genome stability
disease MESH endometrial cancers
disease MESH colorectal cancers
disease MESH gastric cancers
disease MESH Lynch syndrome
disease MESH cancers
disease MESH anxiety
disease MESH schizophrenia
disease MESH major depressive disorder
disease MESH bipolar disorder
disease MESH heart disease
disease MESH abnormalities
disease MESH mutation rate
pathway REACTOME Reproduction
disease MESH vestibular areflexia
disease MESH syndrome
disease MESH gene discovery
disease MESH diagnosis
drug DRUGBANK L-Phenylalanine
disease MESH synpolydactyly
disease MESH holoprosencephaly
disease MESH hand foot genital syndrome
disease MESH Fuchs endothelial corneal dystrophy
disease MESH Desbuquois dysplasia
disease MESH cognitive impairment
disease MESH chorea
drug DRUGBANK Fenamole
disease MESH neuronal intranuclear inclusion disease
disease MESH frontotemporal dementia
pathway KEGG Amyotrophic lateral sclerosis
disease MESH amyotrophic lateral sclerosis
disease MESH cerebellar ataxias
disease MESH Fragile X syndrome
disease MESH myotonic dystrophies
disease MESH muscular dystrophies
disease MESH myoclonic seizures
disease MESH peripheral neuropathies
disease MESH dysarthria
disease MESH gait ataxia
disease MESH atrophy
disease MESH point mutations
disease MESH Myoclonus
disease MESH SCA10
disease MESH FAME1
disease MESH parkinsonism
drug DRUGBANK Levodopa
disease MESH FAME2
disease MESH FAME3
disease MESH essential tremor
disease MESH multiple system atrophy
disease MESH Sjogrens syndrome
disease MESH paraneoplastic syndrome
drug DRUGBANK Indoleacetic acid
disease MESH fasciculations
drug DRUGBANK Gold
drug DRUGBANK Guanine
drug DRUGBANK Cystine
disease MESH stuttering
drug DRUGBANK Trestolone
drug DRUGBANK Alpha-1-proteinase inhibitor
disease MESH Friedreich ataxia
disease MESH Hereditary ataxia
drug DRUGBANK Bean
disease MESH movement disorders
drug DRUGBANK Ferrous sulfate anhydrous
drug DRUGBANK Pentaerythritol tetranitrate
disease MESH Aging
disease MESH tic
disease MESH pathology
disease MESH hypopituitarism
disease MESH hereditary sensory neuropathy
disease MESH scott syndrome
disease MESH X linked mental retardation
drug DRUGBANK Naproxen
disease MESH parkinson disease
pathway KEGG Parkinson disease
disease MESH prion disease
pathway KEGG Prion disease
disease MESH blepharophimosis syndrome
disease MESH neurological manifestations
disease MESH spastic paraplegia
drug DRUGBANK Rasagiline
disease MESH trinucleotide repeat expansion
disease MESH parity

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