Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex

Otero, Brittney A.; Poukalov, Kiril; Hildebrandt, Ryan P.; Thornton, Charles A.; Jinnai, Kenji; Fujimura, Harutoshi; Kimura, Takashi; Hagerman, Katharine A.; Sampson, Jacinda B.; Day, John W.; Wang, Eric T.

doi:10.2139/ssrn.3696782

Cited by 3 publications

(7 citation statements)

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“…The Otero et al (2021) dataset consists of frontal cortex samples from 21 DM1 patients (9 male, 12 female) and 8 controls (4 male, 4 female) (Figure 1B, (23)). The samples were retrieved from frozen brain tissue of adult individuals.…”

Section: Methodsmentioning

confidence: 99%

“…The RNA-Seq was paired-end with a read length of 75 bp. More details can be found in the associated publication (23). The raw RNA-Seq data were downloaded from GEO (study accession: GSE157428).…”

Section: Methodsmentioning

confidence: 99%

“…Here, we set out to create an atlas of all developmentally regulated splicing patterns in the human frontal cortex and studied to what extent they were affected in the brains of DM1 patients. For this, we analyzed publicly available RNA-Seq data from healthy individuals, generated by the BrainSpan and GTEx projects (31, 32), together with recently published data from the brains of DM1 patients and controls (23). In contrast to previous more targeted approaches, this now allowed us to make a comprehensive inventory of splicing events demonstrating a transition towards the fetal state in the DM1 frontal cortex.…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

Degener

Cruchten

Otero

et al. 2021

Preprint

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In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

Degener

Cruchten

Otero

et al. 2021

Preprint

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“…In such cases, a specialized test is performed, sometimes in conjunction with other diagnostic tests. Supporting the ability to effectively assay for repeat expansions, Otero et al have measured repeat expansion in DM1 and DMPK from patients with myotonic dystrophy using OGM and found repeats that ranged up to 15 kbp and they were able to show that the repeat length correlated with the degree of mRNA splicing and severity of symptoms [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Optical Genome Mapping as a Next-Generation Cytogenomic Tool for Detection of Structural and Copy Number Variations for Prenatal Genomic Analyses

Sahajpal

Barseghyan

Kolhe

et al. 2021

Genes

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Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders.

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“…In such cases, a specialized test is performed, sometimes in conjunction with other diagnostic tests. Supporting the ability to effectively assay for repeat expansions, Otero et al have measured repeat expansion in DM1 and DMPK from patients with myotonic dystrophy using OGM and were able to show that the repeat length correlated with the degree of mRNA splicing and severity of symptoms, these repeats ranged up to 15kbp [16].…”

Section: Introductionmentioning

confidence: 99%

Optical genome mapping as a next-generation cytogenomic tool for detection of structural and copy number variations for prenatal genomic analyses

Sahajpal

Barseghyan

Kolhe

et al. 2021

Preprint

View full text Add to dashboard Cite

Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH), and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need of multiple technologies. Optical genome mapping (OGM) is a novel technology that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a next-generation cytogenomic tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential of OGM to become a standard of care in prenatal genetic testing by its ability to identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR based methods or Southern blotting). Also, next-generation sequencing (NGS) methods are excellent at detecting sequencing variants but are unable to accurately detect the repeat regions of the genome which limits the ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal screening test (NIPT) as the standard of care screening assay for all global pregnancies, we anticipate OGM as a high-resolution cytogenomic diagnostic tool employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contra5ction disorders is key to reducing the global burden of genetic disorders.

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Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex

Cited by 3 publications

References 0 publications

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

Optical Genome Mapping as a Next-Generation Cytogenomic Tool for Detection of Structural and Copy Number Variations for Prenatal Genomic Analyses

Optical genome mapping as a next-generation cytogenomic tool for detection of structural and copy number variations for prenatal genomic analyses

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