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  1. Article: Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing.

    Butterfield, Russell J / Dunn, Diane M / Duval, Brett / Moldt, Sarah / Weiss, Robert B

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the chromosome 4q telomere allowing ectopic expression of the DUX4 gene in skeletal ... ...

    Abstract Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the chromosome 4q telomere allowing ectopic expression of the DUX4 gene in skeletal muscle. Genetic analysis is difficult due to the large size and repetitive nature of the array, a nearly identical array on the 10q telomere, and the presence of divergent D4Z4 arrays scattered throughout the genome. Here, we combine nanopore long-read sequencing with Cas9-targeted enrichment of 4q and 10q D4Z4 arrays for comprehensive genetic analysis including determination of the length of the 4q and 10q D4Z4 arrays with base-pair resolution. In the same assay, we differentiate 4q from 10q telomeric sequences, determine A/B haplotype, identify paralogous D4Z4 sequences elsewhere in the genome, and estimate methylation for all CpGs in the array. Asymmetric, length-dependent methylation gradients were observed in the 4q and 10q D4Z4 arrays that reach a hypermethylation point at approximately 10 D4Z4 repeat units, consistent with the known threshold of pathogenic D4Z4 contractions. High resolution analysis of individual D4Z4 repeat methylation revealed areas of low methylation near the CTCF/insulator region and areas of high methylation immediately preceding the DUX4 transcriptional start site. Within the DUX4 exons, we observed a waxing/waning methylation pattern with a 180-nucleotide periodicity, consistent with phased nucleosomes. Targeted nanopore sequencing complements recently developed molecular combing and optical mapping approaches to genetic analysis for FSHD by adding precision of the length measurement, base-pair resolution sequencing, and quantitative methylation analysis.
    Language English
    Publishing date 2023-03-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.17.528868
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Deciphering D4Z4 CpG methylation gradients in fascioscapulohumeral muscular dystrophy using nanopore sequencing.

    Butterfield, Russell J / Dunn, Diane M / Duval, Brett / Moldt, Sarah / Weiss, Robert B

    Genome research

    2023  Volume 33, Issue 9, Page(s) 1439–1454

    Abstract: Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the Chromosome 4q telomere allowing ectopic expression of ... ...

    Abstract Fascioscapulohumeral muscular dystrophy (FSHD) is caused by a unique genetic mechanism that relies on contraction and hypomethylation of the D4Z4 macrosatellite array on the Chromosome 4q telomere allowing ectopic expression of the
    MeSH term(s) Humans ; Muscular Dystrophy, Facioscapulohumeral/genetics ; Nanopore Sequencing ; DNA Methylation ; Protein Processing, Post-Translational ; Chromosomes, Human, Pair 4/genetics ; Chromosomes, Human, Pair 4/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism
    Chemical Substances Homeodomain Proteins
    Language English
    Publishing date 2023-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.277871.123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Population-Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of Statewide Blood Screening Program.

    Johnson, Nicholas E / Butterfield, Russell J / Mayne, Katie / Newcomb, Tara / Imburgia, Carina / Dunn, Diane / Duval, Brett / Feldkamp, Marcia L / Weiss, Robert B

    Neurology

    2021  Volume 96, Issue 7, Page(s) e1045–e1053

    Abstract: Objective: To determine whether the genetic prevalence of the CTG expansion in the : Methods: This study used a cross-sectional cohort of deidentified dried blood spots from the newborn screening program in the state of New York, taken from ... ...

    Abstract Objective: To determine whether the genetic prevalence of the CTG expansion in the
    Methods: This study used a cross-sectional cohort of deidentified dried blood spots from the newborn screening program in the state of New York, taken from consecutive births from 2013 to 2014. Blood spots were screened for the CTG repeat expansion in the
    Results: Of 50,382 consecutive births, there were 24 with a CTG repeat expansion ≥50, consistent with a diagnosis of DM1. This represents a significantly higher DM1 prevalence of 4.76 per 10,000 births (95% confidence interval 2.86-6.67) or 1 in every 2,100 births. There were an additional 96 samples (19.1 per 10,000 or 1 in 525 births) with a CTG expansion in the
    Conclusion: The prevalence of individuals with CTG repeat expansions in
    MeSH term(s) Cross-Sectional Studies ; Female ; Humans ; Infant, Newborn ; Male ; Mass Screening ; Myotonic Dystrophy/epidemiology ; Myotonic Dystrophy/genetics ; Myotonin-Protein Kinase/genetics ; Neonatal Screening ; New York/epidemiology ; Prevalence ; Trinucleotide Repeat Expansion
    Chemical Substances DMPK protein, human ; Myotonin-Protein Kinase (EC 2.7.11.1)
    Language English
    Publishing date 2021-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000011425
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: High throughput screening for expanded CTG repeats in myotonic dystrophy type 1 using melt curve analysis.

    Butterfield, Russell J / Imburgia, Carina / Mayne, Katie / Newcomb, Tara / Dunn, Diane M / Duval, Brett / Feldkamp, Marcia L / Johnson, Nicholas E / Weiss, Robert B

    Molecular genetics & genomic medicine

    2021  Volume 9, Issue 4, Page(s) e1619

    Abstract: Background: Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often ... ...

    Abstract Background: Myotonic dystrophy type 1 (DM1) is caused by CTG repeat expansions in the DMPK gene and is the most common form of muscular dystrophy. Patients can have long delays from onset to diagnosis, since clinical signs and symptoms are often nonspecific and overlapping with other disorders. Clinical genetic testing by Southern blot or triplet-primed PCR (TP-PCR) is technically challenging and cost prohibitive for population surveys.
    Methods: Here, we present a high throughput, low-cost screening tool for CTG repeat expansions using TP-PCR followed by high resolution melt curve analysis with saturating concentrations of SYBR GreenER dye.
    Results: We determined that multimodal melt profiles from the TP-PCR assay are a proxy for amplicon length stoichiometry. In a screen of 10,097 newborn blood spots, melt profile analysis accurately reflected the tri-modal distribution of common alleles from 5 to 35 CTG repeats, and identified the premutation and full expansion alleles.
    Conclusion: We demonstrate that robust detection of expanded CTG repeats in a single tube can be achieved from samples derived from specimens with minimal template DNA such as dried blood spots (DBS). This technique is readily adaptable to large-scale testing programs such as population studies and newborn screening programs.
    MeSH term(s) Costs and Cost Analysis ; High-Throughput Screening Assays/economics ; High-Throughput Screening Assays/methods ; High-Throughput Screening Assays/standards ; Humans ; Molecular Diagnostic Techniques/economics ; Molecular Diagnostic Techniques/methods ; Molecular Diagnostic Techniques/standards ; Myotonic Dystrophy/diagnosis ; Myotonic Dystrophy/genetics ; Nucleic Acid Denaturation ; Sensitivity and Specificity ; Trinucleotide Repeat Expansion
    Language English
    Publishing date 2021-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2734884-2
    ISSN 2324-9269 ; 2324-9269
    ISSN (online) 2324-9269
    ISSN 2324-9269
    DOI 10.1002/mgg3.1619
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Genome degeneration and adaptation in a nascent stage of symbiosis.

    Oakeson, Kelly F / Gil, Rosario / Clayton, Adam L / Dunn, Diane M / von Niederhausern, Andrew C / Hamil, Cindy / Aoyagi, Alex / Duval, Brett / Baca, Amanda / Silva, Francisco J / Vallier, Agnès / Jackson, D Grant / Latorre, Amparo / Weiss, Robert B / Heddi, Abdelaziz / Moya, Andrés / Dale, Colin

    Genome biology and evolution

    2014  Volume 6, Issue 1, Page(s) 76–93

    Abstract: Symbiotic associations between animals and microbes are ubiquitous in nature, with an estimated 15% of all insect species harboring intracellular bacterial symbionts. Most bacterial symbionts share many genomic features including small genomes, ... ...

    Abstract Symbiotic associations between animals and microbes are ubiquitous in nature, with an estimated 15% of all insect species harboring intracellular bacterial symbionts. Most bacterial symbionts share many genomic features including small genomes, nucleotide composition bias, high coding density, and a paucity of mobile DNA, consistent with long-term host association. In this study, we focus on the early stages of genome degeneration in a recently derived insect-bacterial mutualistic intracellular association. We present the complete genome sequence and annotation of Sitophilus oryzae primary endosymbiont (SOPE). We also present the finished genome sequence and annotation of strain HS, a close free-living relative of SOPE and other insect symbionts of the Sodalis-allied clade, whose gene inventory is expected to closely resemble the putative ancestor of this group. Structural, functional, and evolutionary analyses indicate that SOPE has undergone extensive adaptation toward an insect-associated lifestyle in a very short time period. The genome of SOPE is large in size when compared with many ancient bacterial symbionts; however, almost half of the protein-coding genes in SOPE are pseudogenes. There is also evidence for relaxed selection on the remaining intact protein-coding genes. Comparative analyses of the whole-genome sequence of strain HS and SOPE highlight numerous genomic rearrangements, duplications, and deletions facilitated by a recent expansion of insertions sequence elements, some of which appear to have catalyzed adaptive changes. Functional metabolic predictions suggest that SOPE has lost the ability to synthesize several essential amino acids and vitamins. Analyses of the bacterial cell envelope and genes encoding secretion systems suggest that these structures and elements have become simplified in the transition to a mutualistic association.
    MeSH term(s) Adaptation, Physiological ; Animals ; Base Sequence ; Coleoptera/microbiology ; Enterobacteriaceae/genetics ; Evolution, Molecular ; Genome, Bacterial ; Molecular Sequence Data ; Symbiosis/genetics
    Language English
    Publishing date 2014-01-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2495328-3
    ISSN 1759-6653 ; 1759-6653
    ISSN (online) 1759-6653
    ISSN 1759-6653
    DOI 10.1093/gbe/evt210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Evidence-based path to newborn screening for Duchenne muscular dystrophy.

    Mendell, Jerry R / Shilling, Chris / Leslie, Nancy D / Flanigan, Kevin M / al-Dahhak, Roula / Gastier-Foster, Julie / Kneile, Kelley / Dunn, Diane M / Duval, Brett / Aoyagi, Alexander / Hamil, Cindy / Mahmoud, Maha / Roush, Kandice / Bird, Lauren / Rankin, Chelsea / Lilly, Heather / Street, Natalie / Chandrasekar, Ram / Weiss, Robert B

    Annals of neurology

    2012  Volume 71, Issue 3, Page(s) 304–313

    Abstract: Objective: Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we ... ...

    Abstract Objective: Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing.
    Methods: A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification.
    Results: DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP.
    Interpretation: A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations.
    MeSH term(s) Evidence-Based Medicine/methods ; Female ; Humans ; Infant, Newborn ; Male ; Muscular Dystrophy, Duchenne/diagnosis ; Muscular Dystrophy, Duchenne/genetics ; Mutation/genetics ; Neonatal Screening/methods ; Pilot Projects
    Language English
    Publishing date 2012-01-16
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80362-5
    ISSN 1531-8249 ; 0364-5134
    ISSN (online) 1531-8249
    ISSN 0364-5134
    DOI 10.1002/ana.23528
    Database MEDical Literature Analysis and Retrieval System OnLINE

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