Duchenne muscular dystrophy caused by a novel deep intronic <i>DMD</i> mutation

Ginsberg, Matthew R.; McCarty, Andrew; Lacomis, David; Abdel-Hamid, Hoda

doi:10.1002/mus.26073

Cited by 5 publications

(9 citation statements)

References 8 publications

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“…As shown in Table 2 and Figure 1, the largest group consisted of point mutations (Type 1), a type of pseudoexon‐creating mutation that has been previously identified and well‐characterized (Baskin et al, 2011; Bovolenta et al, 2008; Cagliani et al, 2004; Ginsberg et al, 2018; Gonorazky et al, 2016; Greer et al, 2015; Gurvich et al, 2008; Jones et al, 2019; Khelifi et al, 2011; Madden et al, 2009; Magri et al, 2011; Oshima et al, 2009; Zaum et al, 2017). In this cohort, we found eight Type 1a point mutations that created splice donor or acceptor sites (Figure 1a–h), two Type 1a point mutations that removed a decoy splice acceptor site (Figure 1i,j), one Type 1b that creation/disruption an exon splice enhancer/silencer motif (Figure 1k) leading to the utilization of cryptic splice donor and acceptor signals, and a novel class of two Type 1c point mutations that created splice acceptor sites (Figure 1l,m) leading to the formation of pseudo 3ʹ‐terminal exons.…”

Section: Resultsmentioning

confidence: 99%

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

et al. 2022

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DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD

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Section: Resultsmentioning

confidence: 99%

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

et al. 2022

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“…It has been estimated that 30-40% of DMD mutations are de novo [8,16,24]. Every year, new mutations appear, such as complex genomic rearrangements [25], deep intronic mutations that alter splicing patterns [26], etc. These novel, low-frequency mutations in non-hot spot sites demand more accurate diagnostic techniques for individualized management of DMD.…”

Section: Diagnosis Techniques Targeting Mutated Exonsmentioning

confidence: 99%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

119

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Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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“…But no causative alterations were found. Past studies have suggested that deep intronic mutation or splicing mutation with a gene could have deleterious effect, causing human genetic diseases . The further related tests have to be performed in order to identify the pathogenic mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Past studies have suggested that deep intronic mutation or splicing mutation with a gene could have deleterious effect, causing human genetic diseases. [13][14][15][16] The further related tests have to be performed in order to identify the pathogenic mutations. Interestingly, when we carried out mRNA analysis two insertion abnormal transcripts were identified in two Chinese families affected with dystrophinopathy.…”

Section: Casementioning

confidence: 99%

Identification of two novel insertion abnormal transcripts in two Chinese families affected with Dystrophinopathy

Xü

Song

et al. 2019

Clinical Laboratory Analysis

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: Duchenne muscular dystrophy (DMD) is an X-linked recessive inheritance muscle dystrophy disease, associated with pathogenic variants in the DMD gene. MLPA, DHPLC and DMD sequence studies fail to found the causative alteration in two cases. This study intends to evaluate the disease-causing mutations and explains the correlation genotype-phenotype. Methods:The mRNA analysis and Long-range PCR with sequencing were used for molecular diagnosis.Results: In case one, an insertion of 78 nucleotides between exons 40 and 41 (r.573 9_5740insMN602429:r415_492) was identified in case one. The insertion sequences were highly homologous to the intron 40 (NG_012232.1:g.1001760_g.1001837).Long-range PCR with sequencing analysis showed that a novel deep intronic DMD mutation (NG_012232.1:g.1001838A>G) was identified, generating a premature stop codon and terminating protein translation. The likely pathogenic mutation was detected in fetal sample. In case two, an insertion of 74 nucleotides which located inside the consensus sequence AG/GT was detected between exons 2 and 3 (r.93_94insMN584887:r61_134), which resulted in a premature stop codon. The insertion sequences were traceable in the intron 2 of DMD gene (NG_012232.1:g.415926_ g.415999). We did not perform prenatal DMD gene diagnosis for case two due to lack of sufficient genetic information.Conclusion: These findings clarify importance of proceeding to the mRNA analysis when no causative mutations were found neither by MLPA/DHPLC nor gene sequencing so as to reach the molecular confirmation of DMD and carry out an accurate genetic assessment/ carrier status testing. K E Y W O R D ScDNA analysis, duchenne muscular dystrophy, fetal muscle biopsy, prenatal diagnosis, splicing abnormalities

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Duchenne muscular dystrophy caused by a novel deep intronic DMD mutation

Cited by 5 publications

References 8 publications

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Identification of two novel insertion abnormal transcripts in two Chinese families affected with Dystrophinopathy

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