RNA-seq in DMD urinary stem cells recognized muscle-related transcription signatures and addressed the identification of atypical mutations by whole-genome sequencing

Falzarano, Maria Sofia; Grilli, Andrea; Zia, Silvia; Fang, Mingyan; Rossi, Rachele; Gualandi, Francesca; Rimessi, Paola; Dani, Reem El; Fabris, M.; Lǚ, Zhiyuan; Li, Wenyan; Mongini, Tiziana; Ricci, Federica; Pegoraro, Elena; Bello, Luca; Barp, Andrea; Sansone, Valeria; Hegde, Madhuri; Reschiglian, Pierluigi; Bicciato, Silvio; Selvatici, Rita; Ferlini, Alessandra

doi:10.1016/j.xhgg.2021.100054

Cited by 8 publications

(8 citation statements)

References 66 publications

(85 reference statements)

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“…Substantial inversions affecting the DMD gene are an uncommon cause of DMD, with intrachromosomal inversions being exceptionally rare. To date, there have been 14 reported cases of X-chromosomal inversions that disrupt the DMD gene [2,[8][9][10][11][12][13][14][15][16][17][18]. Our research has uncovered two previously undocumented intrachromosomal inversion variants disrupting the DMD gene in patients.…”

Section: Discussionmentioning

confidence: 81%

Identifying inversions with Breakpoints in the Dystrophin Gene through Long-Read Sequencing: Report of Two Cases

Chen,

Luo,

Wang

et al. 2024

Preprint

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Background: Duchenne Muscular Dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, with large deletions being the most frequent type of mutation. Large inversions involving the DMD gene are a less common cause of the disorder, primarily because they often elude detection by standard diagnostic methods such as multiplex ligation probe amplification (MLPA) and whole exome sequencing (WES) utilizing next-generation sequencing (NGS) technologies. Case presentation: Our research uncovered two intrachromosomal inversions involved the dystrophin gene in two unrelated families through Long-read sequencing (LRS). To confirm these variants, Sanger sequencing subsequently carried out. The first case involved a pericentric inversion from DMD intron 47 to the Xq27.3. The second case featured a paracentric inversion between DMD intron 42 and Xp21.1, inherited from the mother. In both cases, simple repeat sequences (SRS) were present at the breakpoints of these inversions. Conclusions: Our findings demonstrate that LRS can be effectively used to detect atypical mutation. The identification of SRS at breakpoints in DMD patients assists in acquiring a more profound understanding of the mechanisms involved in structural variations, thereby facilitating exploration into potential treatments.

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Section: Discussionmentioning

confidence: 81%

Identifying inversions with Breakpoints in the Dystrophin Gene through Long-Read Sequencing: Report of Two Cases

Chen,

Luo,

Wang

et al. 2024

Preprint

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“…Thus, WGS analysis coupled with non-invasive DMD isoforms' transcription studies ( 59 ) is fully feasible and not too expensive, especially if applied to smaller sub-cohorts of patients.…”

Section: Discussionmentioning

confidence: 99%

DMD deletions underlining mild dystrophinopathies: literature review highlights phenotype-related mutation clusters and provides insights about genetic mechanisms and prognosis

Fortunato,

Tonelli,

Farnè

et al. 2024

Front. Neurol.

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DMD gene pathogenic variations cause a spectrum of phenotypes, ranging from severe Duchenne muscular dystrophy, the Becker milder cases, the intermediate or very mild muscle phenotypes invariably characterized by high CK, and the ultrarare fully-asymptomatic cases. Besides these phenotypes, X-linked dilated cardiomyopathy is also caused by DMD mutations. Males carrying DMD deletions with absent or very mild phenotypes have been sparsely described. We performed a horizon scan on public datasets to enroll males with the above phenotypes and carrying DMD deletions to delineate myopathic genotype-phenotype relationships. We inventoried 81 males, who were divided into the following clinical categorization: fully-asymptomatic males aged >43 years (A, N = 22); isolated hyperCKemia (CK, N = 35); and mild weakness (any age) with or without high CK (WCK, N = 24). In all cases, deleted intervals were exons 2 to 55, and no downstream exons were ever involved, apart from an exon 78 deletion in a WCK patient. All deletions were in-frame apart from the known exception to the rule of exon 2 and exon 78. We correlated the mild phenotypes (A and CK) to deleted exons, intronic breakpoints, exon-exon junctions, 3′ isoforms rule, and protein epitopes, and we found that some genetic profiles are exclusively/mainly occurring in A/CK phenotypes, suggesting they are compatible with a quasi-normal muscular performance. We discussed diverse pathogenic mechanisms that may contribute to mild dystrophinopathic phenotypes, and we tried to address some “critical” genetic configurations or exon content needed to preserve a semi-functional DMD gene.

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“…Currently, there are six anti-human dystrophin antibodies for Western blotting that recognize the different domains of dystrophin; one is polyclonal and five are rabbit monoclonal antibodies available from various commercial sources. RNA sequencing (RNA-seq) is a valuable approach for dystrophin mutation detection [ 56 , 57 , 58 , 59 ].…”

Section: Diagnosis Technologymentioning

confidence: 99%

Advances in Dystrophinopathy Diagnosis and Therapy

Saad,

Siciliano,

Angelini

2023

Biomolecules

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Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.

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RNA-seq in DMD urinary stem cells recognized muscle-related transcription signatures and addressed the identification of atypical mutations by whole-genome sequencing

Cited by 8 publications

References 66 publications

Identifying inversions with Breakpoints in the Dystrophin Gene through Long-Read Sequencing: Report of Two Cases

Identifying inversions with Breakpoints in the Dystrophin Gene through Long-Read Sequencing: Report of Two Cases

DMD deletions underlining mild dystrophinopathies: literature review highlights phenotype-related mutation clusters and provides insights about genetic mechanisms and prognosis

Advances in Dystrophinopathy Diagnosis and Therapy

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