Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort

Polavarapu, Kiran; Preethish‐Kumar, Veeramani; Deepha, Sekar; Vengalil, Seena; Nashi, Saraswati; Mahajan, Niranjan Prakash; Thomas, Priya Treesa; Sadasivan, Arun; Warrier, Manjusha G; Gupta, Anupam; Arunachal, Gautham; Debnath, Monojit; Keerthipriya, Muddasu; Pradeep-Chandra-Reddy, Chevula; Puttegowda, Arpitha; John, Anu P.; Tavvala, Ajitha; Gunasekaran, Swetha; Sathyaprabha, Talakad N.; Chandra, Sadanandavalli Retnaswami; Kramer, Boris W.; Delhaas, Tammo; Nalini, Atchayaram

doi:10.1007/s00415-019-09380-3

Cited by 21 publications

(14 citation statements)

References 33 publications

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“…In a Chinese study, the percentage of rearrangements in DMD patients is similar to ours, with 60% of deletions and 9.6% of duplications (Guo et al, 2015) while in an Indian cohort (Polavarapu et al, 2019) there was a higher prevalence of deletions (80%) and only a small percentage of duplications (5%) with a complete absence of the most common exon 2 duplication. In a very large sample population of United Dystrophinopathy Project, Flanigan et al (2009) reported a 43% percentage of deletions and 11% of duplications in all the dystrophinopathy patients (including DMD, BMD, and intermediate phenotypes); the low percentage of deletion compared to the one reported in literature is discussed as due to a selection bias.…”

Section: Dmd Deletions and Duplications: Frequency Distribution Topsupporting

confidence: 83%

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Neri¹,

Rossi²,

Trabanelli³

et al. 2020

Front. Genet.

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in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein d o m a i n , w i t h e ff e c t s on p o p u l a t i o n ge n e t i c c h a r a c t e r i s t i c s a n d ne w personalized therapies.

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Section: Dmd Deletions and Duplications: Frequency Distribution Topsupporting

confidence: 83%

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Neri¹,

Rossi²,

Trabanelli³

et al. 2020

Front. Genet.

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“…The analysis of mutation spectrum has revealed mutations in 80.85% DMD cases with 73% deletions and 7% duplications in unrelated families. Previous Indian studies have reported 75% [16] and 86.6% [22] mutation detection rate by MLPA. Spectrin repeat domain was found to be affected in the majority of cases.…”

Section: Discussionmentioning

confidence: 99%

“…By the time exon skipping therapy becomes costeffective and more technologies emerge with time, there may be an impending requirement to generate a populationspecific DMD mutation database. Majority of the DMD mutation data has been reported from the South Indian population [22] which differs from the North Indian population with respect to ethnic background. Moreover, North Indian studies have been dominated by mPCR and thus may underrepresent the mutation spectrum of DMD gene.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention

Tyagi

Kumar

Dalal

et al. 2020

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Background: Duchenne Muscular Dystrophy (DMD) is a progressive, fatal neuromuscular disorder caused by mutations in the DMD gene. Emerging antisense oligomer based exon skipping therapy provides hope for the restoration of the reading frame. Objectives: Population-based DMD mutation database may enable exon skipping to be used for the benefit of patients. Hence, we planned this study to identify DMD gene variants in North Indian DMD cases. Methods: A total of 100 DMD cases were recruited and Multiplex ligation-dependent probe amplification (MLPA) analysis was performed to obtain the deletion and duplication profile. Results: Copy number variations (deletion/duplication) were found in 80.85% of unrelated DMD cases. Sixty-eight percent of cases were found to have variations in the distal hotspot region (Exon 45- 55) of the DMD gene. Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/ multiple exon variations. As per Leiden databases, 86.84% cases harboured out-of-frame mutations. Domain wise investigation revealed that 68% of mutations were localized in the region of spectrin repeats. Dp140 isoform was predicted to be absent in 62/76 (81.57%) cases. A total of 45/80 (56.25 %) and 23/80 (28.70%) DMD subjects were predicted to be amenable to exon 51 and exon 45 skipping trials, respectively. Conclusion: A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population.

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“…Previously, many studies have been published for NGS-based approaches for MD ( Lim et al, 2011 ; Wang et al, 2014 ; Wei et al, 2014 ; Alame et al, 2016 ). However, there are very few such studies reported for the Indian population ( Aravind et al, 2019 ; Ganapathy et al, 2019 ; Polavarapu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Diagnosis of Muscular Dystrophy Patients in Western Indian Population: A Comprehensive Mutation Analysis Using Amplicon Sequencing

Patel

Bhatt

Shah³

et al. 2021

Front. Genet.

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Muscular Dystrophies (MDs) are a group of inherited diseases and heterogeneous in nature. To date, 40 different genes have been reported for the occurrence and/or progression of MDs. This study was conducted to demonstrate the application of next-generation sequencing (NGS) in developing a time-saving and cost-effective diagnostic method to detect single nucleotide variants (SNVs) and copy number variants (CNVs) in a single test. A total of 123 cases clinically suspected of MD were enrolled in this study. Amplicon panel-based diagnosis was carried out for 102 (DMD/BMD) cases and the results were further screened using multiplex ligation-dependent probe amplification (MLPA). Whilst in the case of LGMD (N = 19) and UMD (N = 2), only NGS panel-based analysis was carried out. We identified the large deletions in 74.50% (76/102) of the cases screened with query DMD or BMD. Further, the large deletion in CAPN3 gene (N = 3) and known SNV mutations (N = 4) were identified in LGMD patients. Together, the total diagnosis rate for this amplicon panel was 70.73% (87/123) which demonstrated the utility of panel-based diagnosis for high throughput, affordable, and time-saving diagnostic strategy. Collectively, present study demonstrates that the panel based NGS sequencing could be superior over to MLPA.

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Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort

Cited by 21 publications

References 33 publications

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention

Molecular Diagnosis of Muscular Dystrophy Patients in Western Indian Population: A Comprehensive Mutation Analysis Using Amplicon Sequencing

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