scholarly journals Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Xia ◽  
Yijie Feng ◽  
Lu Xu ◽  
Xiaoyang Chen ◽  
Feng Gao ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Spinal Muscular Atrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Chinese Family ◽  
Whole Exome

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the DMD gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a Chinese family who present with clinical manifestations of both two diseases, including poor motor development and progressive muscle weakness. We identified a homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene by whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA). This case expands our understanding of diagnosis for synchronous SMA and DMD and highlights the importance of various genetic testing methods, including WES, in differential diagnosis of neuromuscular diseases.

scholarly journals Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

2018 ◽  
Author(s):  
Jose Velilla ◽  
Michael Mario Marchetti ◽  
Agnes Toth-Petroczy ◽  
Claire Grosgogeat ◽  
Alexis H Bennett ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
In Silico ◽  
Muscular Atrophy ◽  
Structural Modeling ◽  
Recessive Mutation ◽  
Homozygous Mutation ◽  
Functional Studies ◽  
Whole Exome

AbstractObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.

scholarly journals The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia

2020 ◽  
Author(s):  
Parisa Amirifar ◽  
Mohammad Reza Ranjouri ◽  
salar Pashangzadeh ◽  
Martin Lavin ◽  
Reza Yazdani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ataxia Telangiectasia ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Public Health Care ◽  
Severe Phenotype ◽  
Whole Exome ◽  
Age Of Diagnosis

Abstract Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.

scholarly journals Novel Partial Exon 51 Deletion in the Duchenne Muscular Dystrophy Gene Identified via Whole Exome Sequencing and Long-Read Whole-Genome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Qianqian Li ◽  
Zhanni Chen ◽  
Hui Xiong ◽  
Ranran Li ◽  
Chenguang Yu ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Whole Exome ◽  
Long Read ◽  
Exonic Deletion

Duchenne muscular dystrophy (DMD), one of the most common progressive and severely disabling neuromuscular diseases in children, can be largely attributed to the loss of function of the DMD gene on chromosome Xp21.2-p21.1. This paper describes the case of a 10-year-old boy diagnosed with DMD. Whole exome sequencing confirmed the hypothesized large partial exonic deletion of c.7310-11543_7359del (chrX:g.31792260_31803852del) spanning exon 51 and intron 50 in DMD. This large deletion was verified to be de novo by PCR, and the two breakpoints were further confirmed by Sanger sequencing and long-read whole-genome sequencing. Notably, this partial exonic deletion was the only complex variation in the deep intron regions or intron–exon junction regions in DMD. In addition, the case study demonstrates the clinical importance of using multiple molecular genetic testing methods for the diagnosis of rare diseases.

scholarly journals Whole exome sequencing of a family revealed a novel variant in the CHM gene, c.22delG p.(Glu8Serfs*4), which co-segregated with choroideremia

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Handong Dan ◽  
Tuo Li ◽  
Xinlan Lei ◽  
Xin Huang ◽  
Yiqiao Xing ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Family Members ◽  
Clinical Manifestations ◽  
Complex Form ◽  
Chinese Family ◽  
Sequencing Data ◽  
Whole Exome ◽  
Novel Variant

Abstract Choroideremia is a complex form of blindness-causing retinal degeneration. The aim of the present study was to investigate the pathogenic variant and molecular etiology associated with choroideremia in a Chinese family. All available family members underwent detailed ophthalmological examinations. Whole exome sequencing, bioinformatics analysis, Sanger sequencing, and co-segregation analysis of family members were used to validate sequencing data and confirm the presence of the disease-causing gene variant. The proband was diagnosed with choroideremia on the basis of clinical manifestations. Whole exome sequencing showed that the proband had a hemizygous variant in the CHM gene, c.22delG p. (Glu8Serfs*4), which was confirmed by Sanger sequencing and found to co-segregate with choroideremia. The variant was classified as likely pathogenic and has not previously been described. These results expand the spectrum of variants in the CHM gene, thus potentially enriching the understanding of the molecular basis of choroideremia. Moreover, they may provide insight for future choroideremia diagnosis and gene therapy.

scholarly journals Facial cleft? The first case of manitoba‐oculo‐tricho‐anal syndrome with novel mutations in China: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuchen Gu ◽  
Yimin Khoong ◽  
Xin Huang ◽  
Tao Zan
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Manifestations ◽  
Sporadic Case ◽  
Facial Cleft ◽  
Ocular Manifestations ◽  
First Case ◽  
Whole Exome ◽  
Chinese Girl ◽  
Low Prevalence

Abstract Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing. Case presentation A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established. Conclusions We discovered the first sporadic case of MOTA syndrome according to clinical manifestations and genetic etiology in the Chinese population. We have identified 2 novel stop-gain mutations in FREM1 gene which further expands the spectrum of mutational seen in the MOTA syndrome. Further research should be conducted for better understanding of its mechanism, establishment of an accurate diagnosis, and eventually the exploitation of a more effective and comprehensive therapeutic intervention for MOTA syndrome.

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