Exonic rearrangements in
            <i>DMD</i>
            in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Ling, Chao; Dai, Yi; Li, Fang; Yao, Feng; Liu, Zhe; Qiu, Zhengqing; Xia, Fan; Zhao, Chen; Zhang, Shuyang; Wang, Kai; Zhang, Xue

doi:10.1002/humu.23953

Cited by 26 publications

(25 citation statements)

References 38 publications

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“…We utilized the circular binary segmentation (CBS) algorithm to predict the recombination event, which is widely used in detecting copy number variations. We found recombination in 2 of the 21 fetuses (P16 with a male fetus and P18 with a female fetus), and the observed frequency (11%) was concordant with the findings of previous reports (6–10%) ( Abbs et al, 1990 ; Nobile et al, 1995 ; Shashi et al, 1996 ; Giliberto et al, 2011 ; Ling et al, 2020 ). Observed recombination sites of these two fetuses were both far away from the disease-causing region and did not interfere with inferring fetal genotypes.…”

Section: Discussionsupporting

confidence: 92%

Haplotype-Based Noninvasive Prenatal Diagnosis of 21 Families With Duchenne Muscular Dystrophy: Real-World Clinical Data in China

Kong

Li²,

Zhao

et al. 2021

Front. Genet.

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Noninvasive prenatal diagnosis (NIPD) of single-gene disorders has recently become the focus of clinical laboratories. However, reports on the clinical application of NIPD of Duchenne muscular dystrophy (DMD) are limited. This study aimed to evaluate the detection performance of haplotype-based NIPD of DMD in a real clinical environment. Twenty-one DMD families at 7–12 weeks of gestation were prospectively recruited. DNA libraries of cell-free DNA from the pregnant and genomic DNA from family members were captured using a custom assay for the enrichment of DMD gene exons and spanning single-nucleotide polymorphisms, followed by next-generation sequencing. Parental haplotype phasing was based on family linkage analysis, and fetal genotyping was inferred using the Bayes factor through target maternal plasma sequencing. Finally, the entire experimental process was promoted in the local clinical laboratory. We recruited 13 complete families, 6 families without paternal samples, and 2 families without probands in which daughter samples were collected. Two different maternal haplotypes were constructed based on family members in all 21 pedigrees at as early as 7 gestational weeks. Among the included families, the fetal genotypes of 20 families were identified at the first blood collection, and a second blood collection was performed for another family due to low fetal concentration. The NIPD result of each family was reported within 1 week. The fetal fraction in maternal cfDNA ranged from 1.87 to 11.68%. In addition, recombination events were assessed in two fetuses. All NIPD results were concordant with the findings of invasive prenatal diagnosis (chorionic villus sampling or amniocentesis). Exon capture and haplotype-based NIPD of DMD are regularly used for DMD genetic diagnosis, carrier screening, and noninvasive prenatal diagnosis in the clinic. Our method, haplotype-based early screening for DMD fetal genotyping via cfDNA sequencing, has high feasibility and accuracy, a short turnaround time, and is inexpensive in a real clinical environment.

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Section: Discussionsupporting

confidence: 92%

Haplotype-Based Noninvasive Prenatal Diagnosis of 21 Families With Duchenne Muscular Dystrophy: Real-World Clinical Data in China

Kong

Li²,

Zhao

et al. 2021

Front. Genet.

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“…Patients with CNVs were detected using a multiplex ligation-dependent probe amplification (MLPA) kit (MRC-Holland, The Netherlands). Patients with SNVs were detected using whole DMD capture and sequencing (NGS + MygenoCap; MyGenotics), as explained previously ( 25 ). Finally, patients without any positive genetic results were recommended for muscle biopsy and RNA sequencing of the muscle tissue.…”

Section: Methodsmentioning

confidence: 99%

A Comprehensive Analysis of 2013 Dystrophinopathies in China: A Report From National Rare Disease Center

Tong¹,

Chang²,

Guan³

et al. 2020

Front. Neurol.

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Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive neuromuscular disorders caused by mutations in DMD. A high-quality database of DMD/BMD is essential not only for clinical practice but also for fundamental research. Here, we aimed to build the largest Chinese national dystrophinopathy database using the National Rare Diseases Registry System of China. Peking Union Medical College Hospital (PUMCH) was the National Rare Diseases Center of China. This research involved 2013 patients with dystrophinopathies, whose diagnoses were confirmed; they were registered and followed up at PUMCH from March 2011 to December 2018. Family history, clinical signs, and treatment data were reported for patients with DMD and BMD at different rates. All six serum biochemical indexes could accurately distinguish between DMD and BMD patients. Copy number variations were the most frequent mutation type (79.2% in DMD and 84.3% in BMD), of which large deletions accounted for 88.4 and 88.6%, large duplications accounted for 11.6 and 11.4% in DMD and BMD, respectively. An exon deletion hotspot, located in exons 45-54, was observed in DMD, and intron 44 was the most frequent deletion starting point (26.5%). Duplication and single nucleotide variations appeared to be uniformly distributed among all exons. Eleven patients were identified to have ultrarare mutation types. Eleven other patients suffered from two separate mutations simultaneously, some of which may have taken place via dependent mechanisms. Thus, we have established the largest hospital-based Chinese dystrophinopathy database via the National Rare Diseases Registry System. This study provides valuable information for further diagnostic and therapeutic studies of dystrophinopathy.

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“…However, it is challenging to define an explicit relationship between DMD CNVs (especially duplications) and the phenotypic spectrum of male carriers. Generally, to assess the potential pathogenicity of CNVs, different databases (Leiden Open Variation Database and UMD-DMD France Database) are consulted for genotype–phenotype correlations of DMD duplications ( Tuffery-Giraud et al, 2009 ; Ling et al, 2020 ). For unreported CNVs, these may be predicted using the frameshift rule and family history.…”

Section: Introductionmentioning

confidence: 99%

Long-Read Sequencing Revealed Extragenic and Intragenic Duplications of Exons 56–61 in DMD in an Asymptomatic Male and a DMD Patient

Bai

Liu

et al. 2022

Front. Genet.

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Expanded carrier screening (ECS) has become an increasingly common technique to assess the genetic risks of individuals in the prenatal or preconception period. Unexpected variants unrelated to referral are being increasingly detected in asymptomatic individuals through ECS. In this study, we reported an asymptomatic male with duplication of exons 56–61 in the DMD gene through ECS using whole-exome sequencing (WES), which was also detected in a male patient diagnosed with typical Duchenne muscular dystrophy (DMD). Breakpoint analysis was then performed to explore the potential mechanisms of phenotypic differences using long-read sequencing (LRS), PacBio single-molecule real-time (PacBio SMRT) target sequencing, and Sanger sequencing. Complex structural variations (SVs) on chromosome X were identified in the asymptomatic male, which revealed that the duplication occurred outside the DMD gene; whereas, the duplication in the patient with DMD was a tandem repeat. The phenotypic differences between the two men could be explained by the different breakpoint junctions. To the best of our knowledge, this is the first report of a breakpoint analysis of DMD duplication in two men with different phenotypes. Breakpoint analysis is necessary when the clinical phenotypes are inconsistent with genotypes, and it applies to prenatal testing.

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Exonic rearrangements in DMD in Chinese Han individuals affected with Duchenne and Becker muscular dystrophies

Cited by 26 publications

References 38 publications

Haplotype-Based Noninvasive Prenatal Diagnosis of 21 Families With Duchenne Muscular Dystrophy: Real-World Clinical Data in China

Haplotype-Based Noninvasive Prenatal Diagnosis of 21 Families With Duchenne Muscular Dystrophy: Real-World Clinical Data in China

A Comprehensive Analysis of 2013 Dystrophinopathies in China: A Report From National Rare Disease Center

Long-Read Sequencing Revealed Extragenic and Intragenic Duplications of Exons 56–61 in DMD in an Asymptomatic Male and a DMD Patient

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