Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan

Okubo, Mariko; Goto, Kanako; Komaki, Hirofumi; Nakamura, Harumasa; Mori‐Yoshimura, Madoka; Hayashi, Yukiko; Mitsuhashi, Satomi; Noguchi, S.; Kimura, En; Nishino, Ichizo

doi:10.1186/s13023-017-0703-4

Cited by 43 publications

(37 citation statements)

References 32 publications

(26 reference statements)

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“…In 180 Polish patients with DMD/BMD, the deletion mainly involved exons 45–54 and exons 3–21 (Zimowski et al, ). In 1,497 Japanese patients with DMD/BMD, exon deletions were most frequently observed in the central hot spot region between exons 45 and 52 (Okubo et al, ), which was consistent with the results of this study (Figure ). Thus, the DMD gene deletion spectrum observed here was similar to that reported in patients with DMD/BMD in Asia, but slightly different from that in patients in Europe and America, which might be due to the limited sample size.…”

Section: Discussionsupporting

confidence: 91%

Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Ling

Dai

et al. 2019

Human Mutation

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Exonic deletions and duplications within DMD are the main pathogenic variants in Duchenne and Becker muscular dystrophies (DMD/BMD). However, few studies have profiled the flanking sequences of breakpoints and the potential mechanism underlying the breakpoints in different fragile regions of DMD. In this study, 896 Chinese male probands afflicted with DMD/BMD were selected from unrelated families and analyzed using multiplex ligation-dependent probe amplification of the DMD gene, in which we identified exon deletions in 784 subjects and duplications in 112 subjects. Deletions occurred most frequently in the genomic region encompassing exons 45-55,accounting for 73% of all deletion patterns. Furthermore, to unravel the potential mechanism that induced breaks, DMD gene capture and sequencing were performed to identify the breakpoints in 37 subjects with deletions encompassing exons 45-55 of DMD; we found that DMD instability did not arise from a single cause; instead, longsequence motifs, nonconsensus microhomologies, low-copy repeats, and microindels were embedded around the breakpoints, which may predispose DMD to instability. In summary, this study highlights the heterogeneous characteristics of the flanking sequences around the breakpoints and helps us to understand the mechanism underlying DMD gene instability.

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Section: Discussionsupporting

confidence: 91%

Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Ling

Dai

et al. 2019

Human Mutation

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“…The deletion and duplication rates were 65.5 and 9.7% respectively. These frequencies are comparable to previous reports of 62–72.2% for deletions and 8.8–13.3% for duplications (Cho et al, ; Deepha et al, ; Guo et al, ; Vieitez et al, ; Rani et al, ; Juan‐Mateu et al, ; Ma et al, ; Mohammed et al, ; Okubo, Goto, et al, , ; Takeshima et al, ; Vengalil et al, ; Xu et al, ; Yang et al, ). The frequencies of large deletions and duplications may appear anomalous in some previous reports because of smaller cohort size or due to use of screening methods that are not able to detect the full spectrum of mutations (Rani et al, ; Vengalil et al, ).…”

Section: Discussionsupporting

confidence: 89%

“…The combined mutation rate of 75.2% for gross deletions and duplications detected by MLPA in our population is similar to frequencies reported in other studies involving larger cohorts of Asian patients. These frequencies range from 70.56% among 1,053 patients (Yang et al, ) to 69.8% among 613 patients (Guo et al, ) in China and around 73% among 1,497 patients in Japan (Okubo et al, a). Additionally, deletion of exon 50 was observed to be the most common exonic deletion in the Singaporean patient cohort, which was similar to other reported studies (Cho et al, ; Flanigan et al, ; Guo et al, ; Lai et al, ; Okubo et al, a).…”

Section: Discussionmentioning

confidence: 99%

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Tomar

Moorthy

Sethi

et al. 2019

American J of Med Genetics Pt C

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Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the DMD gene. Emerging therapies targeting patients with specific mutations are now becoming a reality for many of these patients. Precise molecular diagnosis is essential to facilitate the identification of possible new treatments for patients in the local context. In this study, we screened 145 dystrophinopathic patients in Singapore and assessed their molecular status for eligibility to current emerging genetic therapies. Overall, 140 (96.5%) of all patients harbored pathogenic DMD mutations comprising 95 exonic deletions (65.5%), 14 exonic duplications (9.7%), and 31 pathogenic small mutations (21.4%). Nonsense and frameshift mutations constitute 83.9% of all the small mutations. We found 71% (103/145) of all Singaporean dystrophinopathy patients to be theoretically amenable for exon skipping, either through skipping of single (53.1%) or multiple exons (17.9%).This approach is applicable to 81.1% (77/95) of patients carrying deletions and 83.9% (26/31) of those with small mutations. Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients. Nonsense read-through therapy was found to be applicable in another 12.4% of all patients. Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease. K E Y W O R D SBecker muscular dystrophy, Duchenne muscular dystrophy, dystrophinopathy, genetic diagnosis, mutation spectrum

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“…The large rearrangement including deletions and duplications were detected in 15 patients (11 deletions and 4 duplications), and point mutations were found in 5 patients including nonsense, frameshifts, and splice mutations. The result was consistent with the early reports that large deletions are the most common mutations in the DMD gene accounting for 55-65% and duplications represent up to 5-15%, while, point mutations account for 30% 21,22 . There are two hot spots in DMD gene deletion mutations, exons 1-22 located in the proximal region, and exons 43-55 in the distal region [23][24][25] .…”

Section: Molecular Studiessupporting

confidence: 92%

Genetic Variation Analysis and Treatment Strategy of 20 Patients with Dystrophin Gene Mutations

Liu

Hou

Zhang

et al. 2020

Preprint

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Abstract Introduction.Dystrophin (DMD) gene mutations can affect muscular dystrophin isoform expression and result in progressive muscular dystrophy including Duchenne and Becker muscular dystrophies (DMD and BMD). To establish the correlation between phenotype and genotype and exemplify the current and future treatment for muscular dystrophy disorders, we investigated 20 patients suffering from a dystrophinopathy and summarized clinical manifestation and gene mutations of them.Methods.The clinical manifestations, physical examination, laboratory work, and gene mutation results were collected in 20 patients with DMD or BMD diagnosed by clinical phenotype and genetic sequencing from July 2015 to December 2019. Multiplex ligation probe amplification (MLPA) and next-generation sequencing (NGS) were used to detect mutations in the DMD gene, and detected mutations were confirmed by Sanger sequencing.Results.The clinical manifestation of patients was characterized by progressive symmetrical muscle degeneration, limb weakness, and pseudohypertrophy along with the elevated concentration of creatine kinase, alanine aminotransferase, and aspartate aminotransferase. We found 11 dystrophin gene deletions (55%) and 4 duplication mutations (20%) among the affected patients. However, we also found point mutations including 1 nonsense (20%), 3 frameshifts (60%), and 1 splice sites (20%) mutations in the rest 5 patients. Among the 15 cases of exon deletion or duplication mutations, 7 were inherited from the mother, 3 were de-novo, while the other 5 were not tested. Besides, all 5 point-mutation cases were inherited from the mother, among which 4 point mutations were identified for the first time and linked to the disease phenotype.Conclusions.We provided clinical portraits, genetic results, and the molecular effects of mutations in patients. Four novel point mutations were identified for the first time and associated with the development of DMD and BMD. Further, we expanded knowledge of the DMD variant spectrum and exemplified the emerging therapies in muscular dystrophy.

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Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan

Cited by 43 publications

References 32 publications

Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Genetic Variation Analysis and Treatment Strategy of 20 Patients with Dystrophin Gene Mutations

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