A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene

Zimowski, Janusz; Pilch, Jacek; Pawelec, Magdalena; Purzycka, Joanna; Kubalska, Jolanta; Ziora-Jakutowicz, Karolina; Dudzińska, Magdalena; Zaremba, Jacek

doi:10.1007/s13353-017-0391-8

Cited by 11 publications

(9 citation statements)

References 18 publications

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“…Mutations in the DMD gene lead to a spectrum of diseases, from the severe Duchenne (DMD, #310200) and the milder Becker (BMD, #300376) muscle dystrophies to the isolated dilated cardiomyopathy (#302045) and other mild phenotypes or asymptomatic males. 1 – 3 The frame rule assumes that the functional consequences of DMD mutations are related to the maintaining of the open reading frame, allowing a shorter and partially functional dystrophin to be translated. Therefore, mutations that maintain the frame result in the milder BMD phenotype, whereas out-of-frame mutations cause multiple premature stop codons downstream and are associated with the severe DMD phenotype, although some exceptions occur.…”

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Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

et al. 2021

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ObjectiveGenetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.MethodsWe performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.ResultsWe identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.ConclusionsOur data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.

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confidence: 99%

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

et al. 2021

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“…Although deletions of one or more exons of the DMD gene are almost always pathogenic, several cases with minimal phenotypic expressivity have been reported; examples include asymptomatic males aged over 60 years with deletions of exons 48–51, 48–53 and 45–51 [ 88 , 89 ] or a single exon 48 deletion [ 90 ]. Therefore, when reporting deletions identified as ‘incidental’ findings, it is recommended to state that their penetrance and expressivity is uncertain.…”

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confidence: 99%

EMQN best practice guidelines for genetic testing in dystrophinopathies

et al. 2020

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Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010. These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed.

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“…Deletions of one exon were present in 7 (20.6%) patients -exons 1, 44, 48, 50, and 59, out of which 5 (71.4%) patients had the DMD phenotype. Both patients with the BMD phenotype had single deletions of exon 48, that generally causes a very mild form of the disease 27 .…”

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confidence: 99%

“…In BMD probands, 16 (84.2%) had in-frame mutations, and 3 (15.8%) had out-of-frame mutations (del 44-48; del 44-49; dupl. [18][19][20][21][22][23][24][25][26][27].…”

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confidence: 99%

Analysis of duplications versus deletions in the dystrophin gene in Serbian cohort with dystrophinopathies

et al. 2020

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Background/Aim. Duchenne muscular dystrophy (DMD) and its allelic form Becker muscular dystrophy (BMD) are X-linked diseases that affect males, characterized by progressive muscle and cardiopulmonary weakness, especially in DMD as a severe form of the disease. They result from mutations in the dystrophin gene, and the most common changes are large intragenic deletions and duplications (80%). One third of patients have de novo mutation and 2/3 of the mothers are estimated as carriers. The aim of the study was to analyze the frequency of duplications versus deletions in the dystrophin gene in patients with dystrophinopathies, as well as to analyze the phenotypic effect of large mutations obtained and to determine the carrier status of female relatives in probands with duplications. Methods. We examined 22 DMD and 35 BMD unrelated patients and 6 female relatives of the probands where duplications were found. We used polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) methods, according to the protocol, to detect or confirm mutations in probands and female carriers. Results. In probands, there were 34 (59.6%) large deletions (mostly affected exons 44-60) and 6 (10.5%) large duplications in 4 DMD and 2 BMD patients. Also, duplications were found in 3 out of 4 (75%) tested mothers. The distribution of duplications was heterogeneous, affecting N-terminal and central rod domain, and included more exons, except for one DMD patient who had duplication of exon 2. An exception from the Monaco rule was present in 9.5% of DMD and 15.8% of BMD probands, i.e. in 12.5% of DMD/BMD cases. Conclusion. In 57 DMD/BMD probands, we found 59.6% of large deletions and 10.5% of large duplications. The most affected region of the DMD gene was the central rod domain. An exception to Monaco's rule was present in 12.5% of DMD/BMD cases. Three out of 4 examined proband's mothers were confirmed as carriers.

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A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene

Cited by 11 publications

References 18 publications

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

EMQN best practice guidelines for genetic testing in dystrophinopathies

Analysis of duplications versus deletions in the dystrophin gene in Serbian cohort with dystrophinopathies

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