scholarly journals 99-Case Study of Sporadic Aortic Dissection by Whole Exome Sequencing Indicated Novel Disease-Associated Genes and Variants in Chinese Population

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Zanxin Wang ◽  
Xianmian Zhuang ◽  
Bailang Chen ◽  
Junmin Wen ◽  
Fang Peng ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Pathogenic Variants ◽  
Whole Exome

Background. In this study, the whole exome sequencing in human aortic dissection, a highly lethal cardiovascular disease, was investigated to explore the aortic dissection-associated genes and variants in Chinese population. Methods. Whole exome sequencing was performed in 99 cases of aortic dissection. All single nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and copy number variations (CNVs) were filtered to exclude the benign variants. Enrichment analysis and disease-gene correlation analysis were performed. Results. 3425873 SNPs, 685245 InDels, and 1177 CNVs were identified, and aortic dissection-associated SNPs, InDels, and CNVs were collected. After the disease correlation analysis, 20 candidate genes were identified. Part of these genes such as MYH11, FBN1, and ACTA2 were consistent with previous studies, while MLX, DAB2IP, EP300, ZFYVE9, PML, and PRKCD were newly identified as candidate aortic dissection-associated genes. Conclusion. The pathogenic and likely pathogenic variants in most of AD-associated genes (FBN1, MYH11, EFEMP2, TGFBR2, FBN2, COL3A1, and MYLK) were identified in our cohort study, and pathogenic CNVs involved in MYH11, COL family, and FBN were also identified which are not detectable by other NGS analysis. The correlation between MLX, DAB2IP, EP300, ZFYVE9, PML, PRKCD, and aortic dissection was identified, and EP300 may play a key role in AD.

scholarly journals Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

2018 ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Aortic Disease ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

scholarly journals Identification of candidate genes and pathways in retinopathy of prematurity by whole exome sequencing of preterm infants enriched in phenotypic extremes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang Jin Kim ◽  
◽  
Kemal Sonmez ◽  
Ryan Swan ◽  
J. Peter Campbell ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Preterm Infants ◽  
Premature Infants ◽  
Retinopathy Of Prematurity ◽  
Smooth Endoplasmic Reticulum ◽  
Enrichment Analysis ◽  
Retinal Disease ◽  
Gene Set Enrichment Analysis ◽  
Whole Exome

AbstractRetinopathy of prematurity (ROP) is a vasoproliferative retinal disease affecting premature infants. In addition to prematurity itself and oxygen treatment, genetic factors have been suggested to predispose to ROP. We aimed to identify potentially pathogenic genes and biological pathways associated with ROP by analyzing variants from whole exome sequencing (WES) data of premature infants. As part of a multicenter ROP cohort study, 100 non-Hispanic Caucasian preterm infants enriched in phenotypic extremes were subjected to WES. Gene-based testing was done on coding nonsynonymous variants. Genes showing enrichment of qualifying variants in severe ROP compared to mild or no ROP from gene-based tests with adjustment for gestational age and birth weight were selected for gene set enrichment analysis (GSEA). Mean BW of included infants with pre-plus, type-1 or type 2 ROP including aggressive posterior ROP (n = 58) and mild or no ROP (n = 42) were 744 g and 995 g, respectively. No single genes reached genome-wide significance that could account for a severe phenotype. GSEA identified two significantly associated pathways (smooth endoplasmic reticulum and vitamin C metabolism) after correction for multiple tests. WES of premature infants revealed potential pathways that may be important in the pathogenesis of ROP and in further genetic studies.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

scholarly journals Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

2015 ◽  
Vol 3 (4) ◽  
pp. 283-301 ◽  
Author(s):  
Jesse M. Hunter ◽  
Mary Ellen Ahearn ◽  
Christopher D. Balak ◽  
Winnie S. Liang ◽  
Ahmet Kurdoglu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pathogenic Variants ◽  
Whole Exome

scholarly journals Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

2018 ◽  
Vol 11 (10) ◽  
Author(s):  
Marzia De Bortoli ◽  
Alex V. Postma ◽  
Giulia Poloni ◽  
Martina Calore ◽  
Giovanni Minervini ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Arrhythmogenic Cardiomyopathy ◽  
Pathogenic Variants ◽  
Whole Exome

scholarly journals Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

2017 ◽  
Vol 97 (1) ◽  
pp. 49-59 ◽  
Author(s):  
N. Dinckan ◽  
R. Du ◽  
L.E. Petty ◽  
Z. Coban-Akdemir ◽  
S.N. Jhangiani ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Permanent Teeth ◽  
Tooth Agenesis ◽  
Disease Genes ◽  
Nonsense Mediated Decay ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Complex Inheritance

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

2017 ◽  
Vol 30 (4) ◽  
Author(s):  
Qingwen Zeng ◽  
Yanjie Fan ◽  
Lili Wang ◽  
Zhuo Huang ◽  
Xuefan Gu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Unknown Etiology ◽  
Mendelian Disease ◽  
Atypical Form ◽  
Pathogenic Variants ◽  
Diagnostic Potential ◽  
Whole Exome ◽  
Related Enzyme

AbstractBackground:Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in theCase presentation:Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient’s blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in theConclusions:Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

scholarly journals Whole-exome sequencing analysis on products of conception: A cohort study to evaluate clinical utility and genetic etiology for pregnancy loss

2020 ◽  
Author(s):  
Chen Zhao ◽  
Hongyan Chai ◽  
Qinghua Zhou ◽  
Jiadi Wen ◽  
Uma M. Reddy ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Utility ◽  
Pregnancy Loss ◽  
Renal Diseases ◽  
Sequencing Analysis ◽  
Genetic Etiology ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Products Of Conception

Purpose: Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of whole exome sequencing (WES) in identifying the genetic etiology for pregnancy loss. Methods: A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy number variants were selected for WES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. Results: WES detected six pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multi-system abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders and renal diseases. Conclusion: These results supported the clinical utility of WES for detecting monogenic etiology of pregnancy loss. The identification of disease associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

scholarly journals Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing

2021 ◽  
Vol 13 ◽  
Author(s):  
Lin Sun ◽  
Jianye Zhang ◽  
Ning Su ◽  
Shaowei Zhang ◽  
Feng Yan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Symptoms ◽  
Pathogenic Variants ◽  
Dementia Patients ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Genetic Features ◽  
Standards And Guidelines ◽  
Degenerative Dementia

Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A &gt; G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.

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