Dystrophin gene analysis in Hungarian Duchenne/Becker muscular dystrophy families – Detection of carrier status in symptomatic and asymptomatic female relatives

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.

Download Full-text

P1.1 Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

Neuromuscular Disorders ◽

10.1016/j.nmd.2011.06.761 ◽

2011 ◽

Vol 21 (9-10) ◽

pp. 641-642

Author(s):

N.W. Witting ◽

M.D. Dunoe ◽

J.V. Vissing

Keyword(s):

Muscular Dystrophy ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy

Download Full-text

Molecular diagnosis of Duchenne/Becker muscular dystrophy: enhanced detection of dystrophin gene rearrangements by oligonucleotide array-comparative genomic hybridization

Human Mutation ◽

10.1002/humu.20841 ◽

2008 ◽

Vol 29 (9) ◽

pp. 1100-1107 ◽

Cited By ~ 71

Author(s):

Daniela del Gaudio ◽

Yaping Yang ◽

Barbara A. Boggs ◽

Eric S. Schmitt ◽

Jennifer A. Lee ◽

...

Keyword(s):

Muscular Dystrophy ◽

Comparative Genomic Hybridization ◽

Molecular Diagnosis ◽

Array Comparative Genomic Hybridization ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Oligonucleotide Array ◽

Comparative Genomic ◽

Gene Rearrangements ◽

Genomic Hybridization

Download Full-text

Abstract 468: Previously Unrecognized Intronic Variants in the Dystrophin Gene Identified as Possible Contributors to Dilated Cardiomyopathy

Circulation Research ◽

10.1161/res.127.suppl_1.468 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Alex Gyftopoulos ◽

Tamara Ashvetiya ◽

Yi-Ju Chen ◽

Libin Wang ◽

Charles H Williams ◽

...

Keyword(s):

Heart Failure ◽

Muscular Dystrophy ◽

Dilated Cardiomyopathy ◽

Allele Frequency ◽

Minor Allele Frequency ◽

Mixed Model ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Minor Allele ◽

Intronic Variants

Nonischemic dilated cardiomyopathy (DCM) often has a genetic etiology, however, its prevalence and etiologies are not completely understood. The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals with enrollees 40-69 years of age. Our group created a custom phenotype of heart failure using ICD-10 codes for several subtypes of heart failure diagnoses including DCM. We then compared the individuals included in the custom heart failure phenotype to control individuals in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. We identified 8 unlinked intronic variants in the dystrophin gene ( DMD ) that, when separated by self-identified race, occurred with a combined minor allele frequency of 0.15 in individuals with heart failure who identified as being of African descent. The combined minor allele frequency of these variants was 0.05 in individuals who self-identified as being of European descent. One variant of DMD in particular (rs139029250), was identified with a minor allele frequency of 0.05 in African British with DCM. The unadjusted odds ratio of a diagnosis of heart failure in individuals with rs129029250 was 4.65. When separated by gender, the unadjusted odds ratios are 2.02 for females and 6.44 for males. DMD is most notably known for its role in Duchenne and Becker muscular dystrophy, both of which are known to cause dilated cardiomyopathy in affected individuals. However, none of the individuals (36 female and 43 male) identified in our analysis with rs129029250 have been diagnosed with Duchenne muscular dystrophy, Becker muscular dystrophy, or a primary disorder of muscle (ICD code G70). Additionally, these individuals have an intronic variant of DMD , while Duchene and Becker muscular dystrophy are both due to exonic mutations. These findings suggest a possible common variant in the DMD gene that may contribute to DCM in individuals of African descent.

Download Full-text

Diagnosis of Duchenne/Becker muscular dystrophy and quantitative identification of carrier status by use of entangled solution capillary electrophoresis

Clinical Chemistry ◽

10.1093/clinchem/43.5.745 ◽

1997 ◽

Vol 43 (5) ◽

pp. 745-751 ◽

Cited By ~ 21

Author(s):

Paolo Fortina ◽

Jing Cheng ◽

Mann A Shoffner ◽

Saul Surrey ◽

Wendy M Hitchcock ◽

...

Keyword(s):

Capillary Electrophoresis ◽

Muscular Dystrophy ◽

Genetic Diseases ◽

Becker Muscular Dystrophy ◽

Diagnostic Methods ◽

Carrier Status ◽

Laser Induced Fluorescence Detection ◽

General Utility ◽

Pcr Products ◽

Quantitative Results

Abstract Use of capillary electrophoresis, a new and useful analytical tool, offers a variety of advantages for nucleic acid analyses, including rapid analysis, automation, high resolution, qualitative and quantitative results, and low consumption of both sample and reagents. We report the first example of the use of entangled solution capillary electrophoresis (ESCE) and laser-induced fluorescence detection (LIF) for separation-based diagnostics in the quantitative analysis of multiplex PCR products for determination of carrier status of Duchenne/Becker muscular dystrophy (DMD/BMD). This ap-proach greatly improved the speed, resolution, and sensitivity of information needed for the diagnosis of DMD/BMD compared with that from conventional diagnostic methods, and is of general utility for diagnosis of genetic diseases.

Download Full-text

Proportion and pattern of dystrophin gene deletions in North Indian Duchenne and Becker muscular dystrophy patients

Human Genetics ◽

10.1007/s004390050340 ◽

1997 ◽

Vol 99 (2) ◽

pp. 206-208 ◽

Cited By ~ 15

Author(s):

Vinita Singh ◽

Shirish Sinha ◽

Sudhish Mishra ◽

Lakshmi Shankar Chaturvedi ◽

Sunil Pradhan ◽

...

Keyword(s):

Muscular Dystrophy ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Gene Deletions

Download Full-text

Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Genes ◽

10.3390/genes11070765 ◽

2020 ◽

Vol 11 (7) ◽

pp. 765 ◽

Cited By ~ 1

Author(s):

Kenji Rowel Q. Lim ◽

Narin Sheri ◽

Quynh Nguyen ◽

Toshifumi Yokota

Keyword(s):

Muscular Dystrophy ◽

Molecular Mechanisms ◽

Cardiac Involvement ◽

Gene Mutations ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Female Carrier ◽

Daily Life Activities ◽

Cardiac Manifestations ◽

Available Information

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

Download Full-text