scholarly journals Next-Generation Sequencing Identified Novel Desmoplakin Frame-shift Variant in Patients with Arrhythmogenic Cardiomyopathy

2020 ◽  
Author(s):  
Xiaoping Lin ◽  
Yuankun Ma ◽  
Zhejun Cai ◽  
Qiyuan Wang ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Fatty Infiltration ◽  
Family Members ◽  
Functional Change ◽  
Next Generation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Her Family ◽  
Targeted Next Generation Sequencing ◽  
Frame Shift ◽  
Generation Sequencing

Abstract Background: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. Methods: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed, real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. Results: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant ( c.832delG ) in Desmoplakin ( DSP ) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin ( JUP ) and downregulation of β-catenin, when compared with WT. Conclusion: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

scholarly journals Next-Generation Sequencing Identified Novel Desmoplakin Frame-shift Variant in Patients with Arrhythmogenic Cardiomyopathy

2020 ◽  
Author(s):  
Xiaoping Lin ◽  
Yuankun Ma ◽  
Zhejun Cai ◽  
Qiyuan Wang ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Fatty Infiltration ◽  
Family Members ◽  
Functional Change ◽  
Next Generation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Her Family ◽  
Targeted Next Generation Sequencing ◽  
Frame Shift ◽  
Generation Sequencing

Abstract Background: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. Methods: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed, real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. Results: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant ( c.832delG ) in Desmoplakin ( DSP ) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin ( JUP ) and downregulation of β-catenin, when compared with WT. Conclusion: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

scholarly journals Next-Generation Sequencing Identified Novel Desmoplakin Frame-shift Variant in Patients with Arrhythmogenic Cardiomyopathy

2019 ◽  
Author(s):  
Xiaoping Lin ◽  
Yuankun Ma ◽  
Zhejun Cai ◽  
Qiyuan Wang ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Fatty Infiltration ◽  
Family Members ◽  
Functional Change ◽  
Next Generation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Her Family ◽  
Targeted Next Generation Sequencing ◽  
Frame Shift ◽  
Generation Sequencing

Abstract Background: Arrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown. Methods: A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed, real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. Results: The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of β-catenin, when compared with WT. Conclusion: We infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/β-catenin signaling pathway.

scholarly journals Next-Generation Sequencing Identified Novel Desmoplakin Frame-shift Variant in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy

2019 ◽  
Author(s):  
Xiaoping Lin ◽  
Yuankun Ma ◽  
Zhejun Cai ◽  
Qiyuan Wang ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Fatty Infiltration ◽  
Family Members ◽  
Functional Change ◽  
Next Generation ◽  
Ventricular Cardiomyopathy ◽  
Frame Shift ◽  
Generation Sequencing

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of ARVC. However, the specific etiology in individual families remains largely unknown. Methods A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmid containing the mutation and wild type (WT) was constructed, western-blot and immunofluorescence were performed to detect the functional change due to the mutation. Results The proband, a 56-year-old female, presented with recurrent palpitation and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant ( c.832delG ) in Desmoplakin ( DSP ) among 5 family members. The variant led to a frame-shift and a premature termination codon, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of ARVC. HEK293T cells transfected with mutant expressed truncated DSP protein, upregulation of nuclear junction plakoglobin ( PG ) and downregulation of β-catenin, when compared with WT. Conclusion We infer that the novel c.832delG variant in DSP was associated with ARVC in this family, likely through Wnt/β-catenin signaling pathway.

Identification of a Disease-Causing Mutation in a Chinese Patient with Retinitis Pigmentosa by Targeted Next-Generation Sequencing

2017 ◽  
Vol 27 (6) ◽  
pp. 791-796 ◽  
Author(s):  
Jianping Xiao ◽  
Xueqin Guo ◽  
Yong Wang ◽  
Mingkun Shao ◽  
Xiaoming Wei ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Sanger Sequencing ◽  
Bioinformatics Analysis ◽  
Family Members ◽  
Chinese Patient ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

Purpose To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate disease-causing mutations. Sanger sequencing was performed on all subjects to confirm the candidate mutations and assess cosegregation within the family. Results Clinical examinations of the proband showed typical characteristics of RP. Three candidate heterozygous mutations in 3 genes associated with RP were detected in the proband by targeted NGS. The 3 mutations were confirmed by Sanger sequencing and the deletion (c.357_358delAA) in PRPF31 was shown to cosegregate with RP phenotype in 7 affected family members, but not in 3 unaffected family members. Conclusions The deletion (c.357_358delAA) in PRPF31 was the disease-causing mutation for the proband and his affected family members with RP. To our knowledge, this is the second report of the deletion and the first report of the other 2 mutations in the Chinese population. Targeted NGS combined with bioinformatics analysis proved to be an effective molecular diagnostic tool for RP.

scholarly journals Next-generation sequencing identified novel Desmoplakin frame-shift variant in patients with Arrhythmogenic cardiomyopathy

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoping Lin ◽  
Yuankun Ma ◽  
Zhejun Cai ◽  
Qiyuan Wang ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Frame Shift ◽  
Generation Sequencing

scholarly journals Targeted Next-Generation Sequencing Identifies Separate Causes of Hearing Loss in One Deaf Family and Variable Clinical Manifestations for the p.R161C Mutation in SOX10

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Xiaoyu Yu ◽  
Yun Lin ◽  
Hao Wu
Keyword(s):  
Hearing Loss ◽  
Next Generation Sequencing ◽  
Hypogonadotropic Hypogonadism ◽  
Family Members ◽  
Clinical Manifestations ◽  
Next Generation ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Wide Range ◽  
Generation Sequencing

Hearing loss is the most common sensory deficit in humans. Identifying the genetic cause and genotype-phenotype correlation of hearing loss is sometimes challenging due to extensive clinical and genetic heterogeneity. In this study, we applied targeted next-generation sequencing (NGS) to resolve the genetic etiology of hearing loss in a Chinese Han family with multiple affected family members. Targeted sequencing of 415 deafness-related genes identified the heterozygous c.481C>T (p.R161C) mutation in SOX10 and the homozygous c.235delC (p.L79Cfs∗3) mutation in GJB2 as separate pathogenic mutations in distinct affected family members. The SOX10 c.481C>T (p.R161C) mutation has been previously reported in a Caucasian patient with Kallmann syndrome that features congenital hypogonadotropic hypogonadism with anosmia. In contrast, family members carrying the same p.R161C mutation in this study had variable Waardenburg syndrome-associated phenotypes (hearing loss and/or hair hypopigmentation) without olfactory or reproductive anomalies. Our results highlight the importance of applying comprehensive diagnostic approaches such as NGS in molecular diagnosis of hearing loss and show that the p.R161C mutation in SOX10 may be associated with a wide range of variable clinical manifestations.

scholarly journals Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xueshuang Mei ◽  
Yaqi Zhou ◽  
Muhammad Amjad ◽  
Weiqiang Yang ◽  
Rufei Zhu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Family Members ◽  
Congenital Deafness ◽  
Next Generation ◽  
Single Family ◽  
Genetic Causes ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Profound Deafness ◽  
Generation Sequencing

Background. Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness. Results. Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs ∗ 20) in TECTA, c.3719 G>A (p. Arg1240Gln) in MYO7A, and c.482+1986_1988del in HGF were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked POU3F4 gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing. Conclusions. Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants.

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