Unexpected diagnosis of myotonic dystrophy type 2 repeat expansion by genome sequencing

Rafehi, Haloom; Green, Cherie; Bozaoglu, Kiymet; Gillies, Greta; Delatycki, Martin B.; Lockhart, Paul J.; Scheffer, Ingrid E.; Bahlo, Melanie

doi:10.1038/s41431-022-01166-y

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…These methods are catalogue based, i.e. they will only screen pre-defined STRs and motifs and have been used with great success to diagnose pathogenic REs in disease cohorts [ 4 , 11–13 ]. For example, we recently diagnosed SCA36 in a multigenerational Australian pedigree using ExpansionHunter and exSTRa [ 14 ].…”

Section: Detection and Diagnosis Of Re Disordersmentioning

confidence: 99%

Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future

Rafehi,

Bennett,

Bahlo

2023

Emerging Topics in Life Sciences

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Hereditary cerebellar ataxias are a heterogenous group of progressive neurological disorders that are disproportionately caused by repeat expansions (REs) of short tandem repeats (STRs). Genetic diagnosis for RE disorders such as ataxias are difficult as the current gold standard for diagnosis is repeat-primed PCR assays or Southern blots, neither of which are scalable nor readily available for all STR loci. In the last five years, significant advances have been made in our ability to detect STRs and REs in short-read sequencing data, especially whole-genome sequencing. Given the increasing reliance of genomics in diagnosis of rare diseases, the use of established RE detection pipelines for RE disorders is now a highly feasible and practical first-step alternative to molecular testing methods. In addition, many new pathogenic REs have been discovered in recent years by utilising WGS data. Collectively, genomes are an important resource/platform for further advancements in both the discovery and diagnosis of REs that cause ataxia and will lead to much needed improvement in diagnostic rates for patients with hereditary ataxia.

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Section: Detection and Diagnosis Of Re Disordersmentioning

confidence: 99%

Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future

Rafehi,

Bennett,

Bahlo

2023

Emerging Topics in Life Sciences

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“…Diagnosis of DM2 often requires PCR repeat-primed assay in addition to these. The detection of repeat expansions is limited in WES, but REDs could be screened for using bioinformatic methods for repeat expansions with WGS [84,85].…”

Section: Repeat Expansion Testingmentioning

confidence: 99%

The Diagnostic Landscape of Adult Neurogenetic Disorders

Waung,

Ma,

Wheeler

et al. 2023

Biology

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Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

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“…For example, we recently identified SCA36 as the genetic basis of ataxia in a multi-generational Australian pedigree after a >10-year diagnostic odyssey [ 17 ]. Similarly, the use of these tools in a multi-generational family study of autism spectrum disorder identified a heterozygous intronic CCTG expansion in CNBP , a known cause of myotonic dystrophy type 2 (DM2) [ 18 ]. The identification of novel RE loci using short-read WGS has similarly benefitted from new bioinformatic tools and methodologies.…”

Section: Introductionmentioning

confidence: 99%

Challenges facing repeat expansion identification, characterisation, and the pathway to discovery

Read,

Davies,

Thompson

et al. 2023

Emerging Topics in Life Sciences

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Tandem repeat DNA sequences constitute a significant proportion of the human genome. While previously considered to be functionally inert, these sequences are now broadly accepted as important contributors to genetic diversity. However, the polymorphic nature of these sequences can lead to expansion beyond a gene-specific threshold, causing disease. More than 50 pathogenic repeat expansions have been identified to date, many of which have been discovered in the last decade as a result of advances in sequencing technologies and associated bioinformatic tools. Commonly utilised diagnostic platforms including Sanger sequencing, capillary array electrophoresis, and Southern blot are generally low throughput and are often unable to accurately determine repeat size, composition, and epigenetic signature, which are important when characterising repeat expansions. The rapid advances in bioinformatic tools designed specifically to interrogate short-read sequencing and the development of long-read single molecule sequencing is enabling a new generation of high throughput testing for repeat expansion disorders. In this review, we discuss some of the challenges surrounding the identification and characterisation of disease-causing repeat expansions and the technological advances that are poised to translate the promise of genomic medicine to individuals and families affected by these disorders.

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Unexpected diagnosis of myotonic dystrophy type 2 repeat expansion by genome sequencing

Cited by 7 publications

References 14 publications

Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future

Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future

The Diagnostic Landscape of Adult Neurogenetic Disorders

Challenges facing repeat expansion identification, characterisation, and the pathway to discovery

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