The identification of a novel splicing mutation in the DMD gene of a Chinese family.
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ABSTRACT:
SUBMITTER: Liu W
PROVIDER: S-EPMC8659554 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
Publications
The identification of a novel splicing mutation in the DMD gene of a Chinese family.
Liu Wanlu W Shi Xinwei X Li Yuqi Y Qiao Fuyuan F Wu Yuanyuan Y
Clinical case reports 20211209 12
The proband is a five-year-old boy diagnosed with Duchenne muscular dystrophy (DMD) by clinical manifestations and laboratory examination, but clinical phenotype of his parents is normal. In the study, his mother had a second pregnancy, and they went to obstetrics for genetic counseling to make informed reproductive choices. ...[more]
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Project description:BackgroundPatients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis.MethodsFirst, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified.ResultsMLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient.ConclusionThe pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic.
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Project description:This study was aimed to detect a new mutation responsible for X-linked dilated cardiomyopathy with hyper-CKemia.We studied a proband who presented with cardiac symptoms with hyper-CKemia, but no clinical skeletal involvement in physical examination, laboratory tests, electromyography, echocardiography, and magnetic resonance imaging (MRI) of cardiac muscles. Muscle biopsy for histopathology and immunohistochemistry for accessing sarcolemma changes. The next-generation sequencing and bioinformatics analysis were performed on the patient and Sanger sequencing was confirmed on the other 6 unaffected families.The clinic investigations illustrated a dilated cardiomyopathy. Histopathology and immunohistochemistry showed dystrophic changes and an obvious reduction of dystrophin-N and δ-sarcoglycan, respectively. One hemizygous splicing pathogenic mutation c.31 + 1G > C of exon 1 in the DMD gene (chrX33229398, NM_00 4006) was finally identified in the patient and his nephew, but it was carried in his mother and sister.A novel small mutation was identified at the first exon-intron boundary splicing site by next-generation sequencing and bioinformatics analysis.
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Project description:PurposeTo identify a potential pathogenic mutation in a four-generation Chinese family with X-linked congenital nystagmus (XLCN).MethodsRoutine clinical examination and ophthalmic evaluation were performed on normal controls, two patients and two healthy members of the family. Genomic DNA was prepared from the peripheral blood of members of the family and from 50 normal controls. All coding exons and the intronic boundaries of the four-point-one (4.1), ezrin, radixin, moesin (FERM) domain-containing 7 (FRMD7) gene were amplified using polymerase chain reaction (PCR) followed by direct sequencing.ResultsA previously unreported splicing mutation, c.163-1 G→T transversion (c.163-1 G>T), was detected preceding exon3 of FRMD7 in the patients but not in the unaffected family members and 50 unrelated healthy individuals.ConclusionsWe identified a novel mutation (c.163-1 G→T) of FRMD7 in this Chinese family with XLCN. Our finding is the first report related to c.163-1 G→T mutation in FRMD7. The result expands the mutation spectrum of FRMD7 in association with congenital nystagmus.
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Project description:BackgroundDuchenne muscular dystrophy (DMD, ORPHA:98896) is a lethal X-linked recessive disease that manifests as progressive muscular weakness and wasting. Mutations in the dystrophy gene (DMD) are the main cause of Duchenne muscular dystrophy.Case presentationThis study aims to determine novel mutations of DMD and help preimplantation genetic diagnosis (PGD) for family planning. Here present a 4-year-old Chinses boy with DMD, whole-exome sequencing (WES) was performed to identify the molecular basis of the disease. It was confirmed that the boy carried a novel hemizygous mutation of NC_000023.11(NM_004006.3): c.5912_5922 + 19delinsATGTATG in DMD which inherited from his mother. This led to the aberrant splicing of DMD which demonstrated by a minigene splicing assay and further resulted in the impairment of the dystrophy protein.ConclusionsOur study discovered a novel splicing mutation of DMD in a DMD patient, which expands the variant spectrum of this gene and provide precise genetic diagnosis of DMD for timely therapy. Meanwhile, this finding will supply valuable information for preimplantation genetic diagnosis.
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Project description:BackgroundDesminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including different cardiomyopathies, skeletal myopathy, and arrhythmia. Combined with genotype, it helps us precisely diagnose and treat for desminopathy.MethodsSanger sequencing was used to characterize DES variation, and then a minigene assay was used to verify the effect of splice-site mutation on pre-mRNA splicing. Phenotypes were analyzed based on clinical characteristics associated with desminopathy.ResultsA splicing mutation (c.735+1G>T) in DES was detected in the proband. A minigene assay revealed skipping of the whole exon 3 and transcription of abnormal pre-mRNA lacking 32 codons. Another affected family member who carried the identical mutation, was identified with a novel phenotype of desminopathy, non-compaction of ventricular myocardium. There were 2 different phenotypes varied in cardiomyopathy and skeletal myopathy among the 2 patients, but no significant correlation between genotype and phenotype was identified.ConclusionsWe reported a novel phenotype with a splicing mutation in DES, enlarging the spectrum of phenotype in desminopathy. Molecular studies of desminopathy should promote our understanding of its pathogenesis and provide a precise molecular diagnosis of this disorder, facilitating clinical prevention and treatment at an early stage.
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Project description:IntroductionDuchenne muscular dystrophy (DMD) (NM_004006.3) is one of the most notable neuromuscular disorders of early years. The majority of DMD cases are caused by deletions or duplications in dystrophin, while point mutations are less prevalent in dystrophin abnormalities. It is a common knowledge that the severity of the disease depends on the effect of the mutation on the translational reading frame of the dystrophin mRNA.Case reportWe studied an 8-year-old boy with relevant clinical presentations for DMD. Deletion/duplication screening was performed by using multiplex ligation-dependent probe amplification, and whole-exome sequencing was conducted in order to identify potential variants. A novel de novo splice site variant was identified in the DMD gene (DMD: c.8548-2A>G). To explore the effect of a novel variant in DMD, various in silico analyses were carried out to investigate the pathogenicity of the causative variant. To study the structure of a DMD protein and information on how the genetic variant impacts splicing site in models of wild-type and mutated DMD, we carried out different computational studies. Sanger sequencing was performed for the purpose of variant confirmation and familial segregation analysis.DiscussionThis novel de novo variant was predicted to have an effect on splicing, which leads to DMD due to its significant impacts on dystrophin functionality. The novel mutation would be expected to disrupt the protein structure.
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