Intragenic deletions in the<i>dystrophin</i>gene in 211 Pakistani Duchenne muscular dystrophy patients

Hassan, Muhammad Jawad; Mahmood, Saqib; Ali, Ghazanfar; Bibi, Nazia; Waheed, Ishrat; Rafiq, Muhammad; Ansar, Muhammad; Ahmad, Wasim

doi:10.1111/j.1442-200x.2008.02538.x

Cited by 22 publications

(27 citation statements)

References 30 publications

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“…The frequency of deletion was more common than duplications, similar to frequency reported from other parts of India [23–27]. The reported deletion rates in Pakistanis is 40.7%, Chinese 66.25%, Korean 45.5% and in Taiwanese patients 36%, thus showing possible variations among different populations [22, 28–30]. The duplication rate in our cases mainly involved larger fragments and the pattern of duplication was more towards the distal part of the gene unlike other populations [22].…”

Section: Discussionsupporting

confidence: 78%

MLPA identification of dystrophin mutations and in silico evaluation of the predicted protein in dystrophinopathy cases from India

Deepha¹,

Vengalil

Preethish‐Kumar

et al. 2017

BMC Med Genet

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BackgroundDuchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders caused by mutations in the DMD gene. The aim of this study was to predict the effect of gene mutations on the dystrophin protein and study its impact on clinical phenotype.MethodsIn this study, 415 clinically diagnosed patients were tested for mutations by Multiplex ligation dependent probe amplification (MLPA). Muscle biopsy was performed in 34 patients with negative MLPA. Phenotype-genotype correlation was done using PROVEAN, hydrophobicity and eDystrophin analysis. We have utilized bioinformatics tools in order to evaluate the observed mutations both at the level of primary as well as secondary structure.ResultsMutations were identified in 75.42% cases, of which there were deletions in 91.6% and duplications in 8.30%. As per the reading frame rule, 84.6% out-of frame and 15.3% in-frame mutations were noted. Exon 50 was the most frequently deleted exon and the exon 45–52 region was the hot-spot for deletions in this cohort. There was no correlation noted between age of onset or creatine kinase (CK) values with extent of gene mutation. The PROVEAN analysis showed a deleterious effect in 94.5% cases and a neutral effect in 5.09% cases. Mutations in exon 45–54 (out of frame) and exon 46–54 (in-frame) regions in the central rod domain of dystrophin showed more negative scores compared to other domains in the present study. Hydrophobicity profile analysis showed that the hydrophobic regions I & III were equally affected. Analysis of deletions in hinge III hydrophobic region by the eDystrophin programme also predicted a hybrid repeat seen to be associated with a BMD like disease progression, thus making the hinge III region relatively tolerant to mutations.ConclusionsWe found that, while the predictions made by the software utilized might have overall significance, the results were not convincing on a case by case basis. This reflects the inadequacy of the currently available tools and also underlines the possible inadequacy of MLPA to detect other minor mutations that might enhance or suppress the effect of the primary mutation in this large gene. Next Generation Sequencing or targeted Sanger sequencing on a case by case basis might improve phenotype- genotype correlation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0431-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

MLPA identification of dystrophin mutations and in silico evaluation of the predicted protein in dystrophinopathy cases from India

Deepha¹,

Vengalil

Preethish‐Kumar

et al. 2017

BMC Med Genet

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“…Presently, deletions almost involved hot spots residing on the mid-distal exons of dystrophin gene (exons 45-50) as previously reported in various studies [10][11][12]. Exons 50 was the most frequently deleted exon which is in the line with previous report of Pakistani population analyzed by M-PCR alone [13]. The least frequent deletions were attributed to proximal (5 0 ) and distal (3 0 ) exons.…”

Section: Novel Mutation Identified By Sequencingsupporting

confidence: 80%

“…Using M-PCR, we could detect all of the deletions including large ones similar to other studies on Taiwanese and Pakistani patients [24]. However, inability to detect intragenic gene rearrangements especially large deletions or duplications has been described as one of the major drawbacks of M-PCR [13]. MLPA or quantitative PCR are alternative methods to characterize the female carriers and duplications [21].…”

Section: Novel Mutation Identified By Sequencingmentioning

confidence: 77%

“…Duplications are the least common type of mutations in BMD and DMD patients. Some specific exons have been introduced as hot spots which include exons 1, 3,4,5,13,19, 60 and the adjacent exons 42-53 (except of exons 46 and 49). There are different methods to detect various types of DMD gene's mutations as well as southern blotting, multiplex amplifiable probe hybridization (MAPH), quantitative PCR, fluorescent in situ hybridization (FISH), sequencing for checking point mutations [3], multiplex ligation-dependent probe amplification (MLPA) and multiplex PCR (M-PCR).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of dystrophin gene in Iranian Duchenne and Becker muscular dystrophies patients and identification of a novel mutation

et al. 2015

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Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most frequent muscular dystrophies. Present study aimed to determine the frequency of dystrophin gene alterations in Iranian DMD/BMD patients using molecular techniques. 146 Iranian DMD/BMD patients have been analyzed using two devised sets of multiplex polymerase chain reaction (M-PCR) followed by multiple ligation-dependent probe amplification (MLPA). Two isolated DMD and BMD patients were analyzed by DNA sequencing. 30.9 % of patients had single-exon deletion while group and contiguous exon deletions were identified in 41 % of the patients. The most numerous exon deletions included exons 45-50 and were identified in the first M-PCR set. Deletion detection rate was 99 % in first M-PCR set and remaining deletions (1 %) were identified in the second M-PCR set. MLPA analysis showed that there were two exons 3-5 and 41-43 duplications (1.4 %) in a BMD and a DMD patient, respectively. Two nonsense mutations including c.633dupA and c.6283 C>T were, respectively, found in a DMD and BMD patient in which c.633dupA has not ever been reported in DMD mutation database and was pathogenic mutation. Besides the report of frequency of dystrophin gene alteration in a subset of Iranian DMD/BMD patients, it was revealed that the proposed M-PCR protocol can be useful in the initial step of molecular diagnosis of DMD/BMD. Exon sequencing would be the final step in determining the mutation status of DMD/BMD patients following MLPA.

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“…[32] The deletion rate in our study was about 73% and was similar to the frequency reported from the other parts of India. [33] The reported frequency of dystrophin gene deletions in other countries in Asia is quite variable: 40.7% in Pakistan, [34] and 66.25% in China. [35] In Egypt, an African country, it was 61.1%.…”

Section: Carrier Testingmentioning

confidence: 97%

Duchenne muscular dystrophy: A clinical, histopathological and genetic study at a neurology tertiary care center in southern India

Swaminathan

Shubha

et al. 2009

Neurol India

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Intragenic deletions in thedystrophingene in 211 Pakistani Duchenne muscular dystrophy patients

Abstract: The observed proportion of intragenic deletions in the Pakistani population is relatively low, which is comparable with most of the Asian data. Also, deletions in 67 patients (77.9%) are in agreement with the frame-shift rule.

Cited by 22 publications

References 30 publications

MLPA identification of dystrophin mutations and in silico evaluation of the predicted protein in dystrophinopathy cases from India

MLPA identification of dystrophin mutations and in silico evaluation of the predicted protein in dystrophinopathy cases from India

Analysis of dystrophin gene in Iranian Duchenne and Becker muscular dystrophies patients and identification of a novel mutation

Duchenne muscular dystrophy: A clinical, histopathological and genetic study at a neurology tertiary care center in southern India

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