Dataset Information

Risk assessment and genetic counseling in families with Duchenne muscular dystrophy.

ABSTRACT: The Duchenne Muscular dystrophy (DMD) is the most frequent muscle disorder in childhood caused by mutations in the Xlinked dystrophin gene (about 65% deletions, about 7% duplications, about 26% point mutations and about 2% unknown mutations). The clinically milder Becker muscular dystrophy (BMD) is allelic to DMD. About 33% of all patients are due to de novo mutations and germ line mosaicism is frequently observed. While in earlier studies equal mutation rates in males and females had been reported, a breakdown by mutation types can better explain the sex ratio of mutations: Point mutations and duplications arise preferentially during spermatogenesis whereas deletions mostly arise in oogenesis. With current analytical methods, the underlying mutation can be identified in the great majority of cases and be used for carrier detection. However, in families with no mutation carrier available, the genetic model to be used for counselling of relatives can be quite complex.

SUBMITTER: Grimm T

PROVIDER: S-EPMC3631803 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Risk assessment and genetic counseling in families with Duchenne muscular dystrophy.

Grimm Tiemo T Kress Wolfram W Meng Gerhard G Müller Clemens R CR

Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 20121201 3

The Duchenne Muscular dystrophy (DMD) is the most frequent muscle disorder in childhood caused by mutations in the Xlinked dystrophin gene (about 65% deletions, about 7% duplications, about 26% point mutations and about 2% unknown mutations). The clinically milder Becker muscular dystrophy (BMD) is allelic to DMD. About 33% of all patients are due to de novo mutations and germ line mosaicism is frequently observed. While in earlier studies equal mutation rates in males and females had been repor ...[more]

PMID: 23620649

Similar Datasets

Project description:BACKGROUND:Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children, and there are no effective therapies for DMD or Becker Muscular Dystrophy (BMD). Currently, targeted gene therapy treatments have emerged. As a result, genetic diagnosis is the basis of treatment. In addition, genetic and prenatal diagnosis significantly reduces their incidence rates. This study combines the application of multiplex ligation-dependent probe amplification technology (MLPA) and "next-generation" sequencing technology (NGS) as the most economical and efficient method of diagnosis. Therefore, in the diagnosis of DMD/BMD, patients' MLPA data are first used to detect DMD gene deletions or duplications, and NGS and Sanger sequencing are then applied to exclude MLPA-negative samples. Meanwhile, polymerase chain reaction (PCR) is used to detect single exon deletions to exclude false-positives in MLPA caused by point mutations. METHODS:In this study, we recruited 1051 proband families of DMD from 2016 to 2018 and had access to information that could identify individual participants during or after data collection. Patients who were diagnosed with DMD were first tested by MLPA. MLPA results with single exon deletions were validated with PCR amplification and Sanger sequencing. The negative results of MLPA were further analysed with NGS and validated by Sanger sequencing. For novel missense mutations, phenotype-genotype correlations were analysed using PolyPhen2 and mutation taster. All methods were performed in accordance with the relevant guidelines and regulations. RESULTS:DMD mutations were identified in 1029 families (97.91%, 1029/1051). Large deletions, duplications, and small mutations accounted for 70.41% (740/1051), 8.28% (87/1051), and 19.12% (201/1051) of all cases, respectively. There were 205 small mutation types, 53 of which were novel. The rate of de novo mutations was 39.45% (187/474) and was higher in large duplications (49.53%, 157/317). Among 68 asymptomatic patients (<?3?years old) with unexplained persistent hyperCKaemia upon conventional physical examination, 63 were diagnosed as DMD/BMD according to genetic diagnosis. CONCLUSION:Our results expand the spectrum of DMD mutations, which could contribute to the treatment of DMD/BMD and provide an effective diagnosis method. Thus, the combination of MLPA, NGS and Sanger sequencing is of great significance for family analysis, gene diagnosis and gene therapy.

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

Risk assessment and genetic counseling in families with Duchenne muscular dystrophy.

Publications

Risk assessment and genetic counseling in families with Duchenne muscular dystrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets