A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis

Xü, Ying; Liu, Yu; Song, Tingting; Guo, Fenfen; Zheng, Jin; Hui, Xu; Feng, Yi; Cheng, Lu; Li, Chunyan; Chen, Biliang; Zhang, Jianfang

doi:10.1002/jcla.22445

Cited by 7 publications

(11 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The deletion and duplication rates were 65.5 and 9.7% respectively. These frequencies are comparable to previous reports of 62–72.2% for deletions and 8.8–13.3% for duplications (Cho et al, ; Deepha et al, ; Guo et al, ; Vieitez et al, ; Rani et al, ; Juan‐Mateu et al, ; Ma et al, ; Mohammed et al, ; Okubo, Goto, et al, , ; Takeshima et al, ; Vengalil et al, ; Xu et al, ; Yang et al, ). The frequencies of large deletions and duplications may appear anomalous in some previous reports because of smaller cohort size or due to use of screening methods that are not able to detect the full spectrum of mutations (Rani et al, ; Vengalil et al, ).…”

Section: Discussionsupporting

confidence: 89%

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Tomar

Moorthy

Sethi

et al. 2019

American J of Med Genetics Pt C

View full text Add to dashboard Cite

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the DMD gene. Emerging therapies targeting patients with specific mutations are now becoming a reality for many of these patients. Precise molecular diagnosis is essential to facilitate the identification of possible new treatments for patients in the local context. In this study, we screened 145 dystrophinopathic patients in Singapore and assessed their molecular status for eligibility to current emerging genetic therapies. Overall, 140 (96.5%) of all patients harbored pathogenic DMD mutations comprising 95 exonic deletions (65.5%), 14 exonic duplications (9.7%), and 31 pathogenic small mutations (21.4%). Nonsense and frameshift mutations constitute 83.9% of all the small mutations. We found 71% (103/145) of all Singaporean dystrophinopathy patients to be theoretically amenable for exon skipping, either through skipping of single (53.1%) or multiple exons (17.9%).This approach is applicable to 81.1% (77/95) of patients carrying deletions and 83.9% (26/31) of those with small mutations. Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients. Nonsense read-through therapy was found to be applicable in another 12.4% of all patients. Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease. K E Y W O R D SBecker muscular dystrophy, Duchenne muscular dystrophy, dystrophinopathy, genetic diagnosis, mutation spectrum

show abstract

Section: Discussionsupporting

confidence: 89%

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Tomar

Moorthy

Sethi

et al. 2019

American J of Med Genetics Pt C

View full text Add to dashboard Cite

show abstract

“…Genomic DNA was extracted from blood and amniotic fluid as described before. 6 The previous MLPA/DHPLC and DMD sequence studies but no mutations were identified. Total RNA was extracted from patients, related relatives, and control amniotic fluid or muscle samples using the TianGen RNA simple total RNA extraction kit (TianGen, DP419) according to the manufacturer's instructions.…”

Section: Pathogenic Mutations Detectionmentioning

confidence: 94%

“…Amniotic fluid sample was collected by following the standard procedures as described by our previous report. 6 And fetal muscle biopsy was carried out using a double needle 18 gauge for the guide, 20 gauges for the second needle (Modena, PNM0418-1) under transabdominal ultrasonographic guidance. The needle must be heparinized to avoid clots and located directly over the fetal thigh muscle.…”

Section: Study Subjects and Fetal Sample Collectionmentioning

confidence: 99%

“…5 We previously identified 237 Chinese families with DMD history using DHPLC to detect deletions and duplications of patients and Sanger sequencing of the coding region and splice sites to detect point mutations. 6 However, approximately 1%-2% of the dystrophinopathy patients are principally caused by deep intronic alterations or other regulatory alterations. These mutations must be altering the normal processing of the mRNA.…”

Section: Introductionmentioning

confidence: 99%

“…The molecular characterization of deleterious mutations has been considered an endpoint for genetic diagnosis of genetic diseases . We previously identified 237 Chinese families with DMD history using DHPLC to detect deletions and duplications of patients and Sanger sequencing of the coding region and splice sites to detect point mutations . However, approximately 1%‐2% of the dystrophinopathy patients are principally caused by deep intronic alterations or other regulatory alterations.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of two novel insertion abnormal transcripts in two Chinese families affected with Dystrophinopathy

Xü

Song

et al. 2019

Clinical Laboratory Analysis

Self Cite

View full text Add to dashboard Cite

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: Duchenne muscular dystrophy (DMD) is an X-linked recessive inheritance muscle dystrophy disease, associated with pathogenic variants in the DMD gene. MLPA, DHPLC and DMD sequence studies fail to found the causative alteration in two cases. This study intends to evaluate the disease-causing mutations and explains the correlation genotype-phenotype. Methods:The mRNA analysis and Long-range PCR with sequencing were used for molecular diagnosis.Results: In case one, an insertion of 78 nucleotides between exons 40 and 41 (r.573 9_5740insMN602429:r415_492) was identified in case one. The insertion sequences were highly homologous to the intron 40 (NG_012232.1:g.1001760_g.1001837).Long-range PCR with sequencing analysis showed that a novel deep intronic DMD mutation (NG_012232.1:g.1001838A>G) was identified, generating a premature stop codon and terminating protein translation. The likely pathogenic mutation was detected in fetal sample. In case two, an insertion of 74 nucleotides which located inside the consensus sequence AG/GT was detected between exons 2 and 3 (r.93_94insMN584887:r61_134), which resulted in a premature stop codon. The insertion sequences were traceable in the intron 2 of DMD gene (NG_012232.1:g.415926_ g.415999). We did not perform prenatal DMD gene diagnosis for case two due to lack of sufficient genetic information.Conclusion: These findings clarify importance of proceeding to the mRNA analysis when no causative mutations were found neither by MLPA/DHPLC nor gene sequencing so as to reach the molecular confirmation of DMD and carry out an accurate genetic assessment/ carrier status testing. K E Y W O R D ScDNA analysis, duchenne muscular dystrophy, fetal muscle biopsy, prenatal diagnosis, splicing abnormalities

show abstract

DMD‐related muscular dystrophy in Cameroon: Clinical and genetic profiles

Wonkam‐Tingang

Nguefack

Esterhuizen

et al. 2020

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background Most of the previous studies on Duchenne Muscular Dystrophy (DMD) were conducted in Caucasian, Asian, and Arab populations. Therefore, little is known about the features of this disease in Africans. In this study, we aimed to determine the clinical characteristics of DMD, and the common mutations associated with this condition in a group of Cameroonian patients. Methods We recruited DMD patients and performed a general physical examination on each of them. Multiplex ligand‐dependant probe amplification was carried out to investigate exon deletions and duplications in the DMD gene (OMIM: 300377) of patients and their mothers. Results A total of 17 male patients from 14 families were recruited, aged 14 ± 5.1 (8–23) years. The mean age at onset of symptoms was 4.6 ± 1.5 years, and the mean age at diagnosis was 12.1 ± 5.2 years. Proximal muscle weakness was noted in all patients and calf hypertrophy in the large majority of them (88.2%; 15/17). Flexion contractures were particularly frequent on the ankle (85.7%; 12/14). Wasting of shoulder girdle and thigh muscles was present in 50% (6/12) and 46.2% (6/13) of patients, respectively. No patient presented with hearing impairment. Deletions in DMD gene (OMIM: 300377) occurred in 45.5% of patients (5/11), while duplications were observed in 27.3% (3/11). Both mutation types were clustered between exons 45 and 50, and the proportion of de novo mutation was estimated at 18.2% (2/11). Conclusion Despite the first symptoms of DMD occurring in infancy, the diagnosis is frequently made later in adolescence, indicating an underestimation of the number of cases of DMD in Cameroon. Future screening of deletions and duplications in patients from Cameroon should focus on the distal part of the gene.

show abstract

A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis

Abstract: DHPLC and Sanger sequencing technique are efficient, sensitive, and specific in screening for DMD gene mutations. And pre-pregnancy DMD gene examination is an important step to assess mutation type of family with suspected DMD and guides exactly prenatal diagnosis in high-risk families.

Cited by 7 publications

References 35 publications

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Identification of two novel insertion abnormal transcripts in two Chinese families affected with Dystrophinopathy

DMD‐related muscular dystrophy in Cameroon: Clinical and genetic profiles

Contact Info

Product

Resources

About