30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

Depienne, Christel; Mandel, Jean‐Louis

doi:10.1016/j.ajhg.2021.03.011

Cited by 261 publications

(246 citation statements)

References 168 publications

Supporting

Mentioning

243

Contrasting

Order By: Relevance

“…All the above provided the evidence for the association between the CGG repeat expansion in RILPL1 and OPDM in our study. Considering RNA toxicity is a common mechanism behind many human neurological diseases and disorders caused by abnormal non-coding trinucleotide repeat expansions[2, 5, 16], we further examined whether it was the case for OPDM. According to gene structures annotated by RefSeq, Ensembl and GENCODE, the CGG repeat is located 3bp upstream of RILPL1 gene (Material and Methods, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

Yang

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

Oculopharyngodistal myopathy is an adult-onset degenerative muscle disorder characterized by ptosis, ophthalmoplegia and weakness of the facial, pharyngeal and limb muscles. Trinucleotide repeat expansions in non-coding regions of LRP12, G1PC1and NOTCH2NLC were recently reported to be the etiologies for OPDM. However, a significant portion of OPDM patients still have unknown genetic causes. In this study, we performed long-read whole-genome sequencing in a large five-generation family of 156 individuals, including 22 patients diagnosed with typical OPDM and identified CGG repeat expansions in RILPL1 gene in all patients we tested while not in unaffected family members. Methylation analysis indicated that methylation levels of the RILPL1 gene were unaltered in OPDM patients, which was in consistent with previous reports. Our findings first provided evidences that RILPL1 were associated OPDM which we suggested as OPDM type 4.

show abstract

Section: Resultsmentioning

confidence: 99%

Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

Yang

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…HD-like syndromes may be caused by other STR genes that were also included on our targeted sequencing panel (i.e., C9orf72, PRNP, JPH3, TBP, ATXN8, FXN and ATN1) (3,4). Parallel sequencing of these genes showed that all HD-affected patients harboured STR alleles within healthy ranges (Fig.…”

Section: Huntington's Disease (Hd)mentioning

confidence: 99%

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Stevanovski

Chintalaphani

Gamaarachchi

et al. 2021

Preprint

View full text Add to dashboard Cite

Short-tandem repeat (STR) expansions are an important class of pathogenic genetic variants. Over forty neurological and neuromuscular diseases are caused by STR expansions, with 37 different genes implicated to date. Here we describe the use of programmable targeted long-read sequencing with Oxford Nanopore's ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single, simple assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of expanded and non-expanded STR sites. In doing so, the assay correctly diagnoses all individuals in a cohort of patients (n = 27) with various neurogenetic diseases, including Huntington's disease, fragile X syndrome, cerebellar ataxia (CANVAS) and others. Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing, and identifies non-canonical STR motif conformations and internal sequence interruptions. Even in our relatively small cohort, we observe a wide diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of STR expansion disorders. Finally, we show how the flexible inclusion of pharmacogenomics (PGx) genes as secondary ReadUntil targets can identify clinically actionable PGx genotypes to further inform patient care, at no extra cost. Our study addresses the need for improved techniques for genetic diagnosis of STR expansion disorders and illustrates the broad utility of programmable long-read sequencing for clinical genomics.

show abstract

“…Many studies, including one describing the use of Oxford Nanopore long-read technology to study the Icelandic population ( 117 , 144–148 ), reaffirm the need to consider large-scale copy number and structural variation in disease study design. In our own recent research, developing novel computational and statistical methods to analyze existing short-read sequence data for expanded tandem repeats led to the discovery of specific loci associated with autism ( 149 ), an intriguing finding given that most known disorders associated with tandem repeat expansions are monogenic ( 150 ). The same study also discovered extensive polymorphism in repeat motif size and sequence, often correlated with cytogenetic ‘fragile site’ variation along chromosomes ( 149 ).…”

Section: Redefining Genomic Variation Using Short- and Long-read Wgsmentioning

confidence: 99%

Discovery of genomic variation across a generation

Trost

Loureiro

Scherer

2021

Human Molecular Genetics

View full text Add to dashboard Cite

Over the past thirty years (the timespan of a generation), advances in genomics technologies have revealed tremendous and unexpected variation in the human genome and have provided increasingly accurate answers to long-standing questions of how much genetic variation exists in human populations and to what degree the DNA complement changes between parents and offspring. Tracking the characteristics of these inherited and spontaneous (or de novo) variations has been the basis of the study of human genetic disease. From genome-wide microarray and next-generation sequencing scans, we now know that each human genome contains over 3 million single nucleotide variants when compared to the ~ 3 billion base pairs in the human reference genome, along with roughly an order of magnitude more DNA—approximately 30 megabase pairs (Mb)—being ‘structurally variable’, mostly in the form of indels and copy number changes. Additional large-scale variations include balanced inversions (average of 18 Mb) and complex, difficult-to-resolve alterations. Collectively, about 1% of an individual’s genome will differ from the human reference sequence. When comparing across a generation, fewer than 100 new genetic variants are typically detected in the euchromatic portion of a child’s genome. Driven by increasingly higher-resolution and higher-throughput sequencing technologies, newer and more accurate databases of genetic variation (for instance, more comprehensive structural variation data and phasing of combinations of variants along chromosomes) of worldwide populations will emerge to underpin the next era of discovery in human molecular genetics.

show abstract

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

Cited by 261 publications

References 168 publications

Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Discovery of genomic variation across a generation

Contact Info

Product

Resources

About