scholarly journals Whole-exome sequencing identifies multiple pathogenic variants in a large South Indian family with primary open-angle glaucoma

2021 ◽  
Vol 69 (9) ◽  
pp. 2461
Author(s):  
Periasamy Sundaresan ◽  
MohdHussain Shah ◽  
Manojkumar Kumaran ◽  
Prakash Chermakani ◽  
MohideenAbdul Kader ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Open Angle ◽  
Indian Family ◽  
Pathogenic Variants ◽  
South Indian ◽  
Whole Exome

scholarly journals Whole Exome Sequencing identifies multiple pathogenic variants in a large south Indian family with Primary Open Angle Glaucoma

2020 ◽  
Author(s):  
Mohd Hussain Shah ◽  
Manojkumar Kumaran ◽  
Prakash Chermakani ◽  
Mohideen Abdul Kader ◽  
R. Ramakrishnan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Low Frequency ◽  
Open Angle ◽  
Indian Family ◽  
Pathogenic Variants ◽  
South Indian ◽  
Whole Exome

AbstractPurposeTo identify the pathogenic variants associated with POAG by using Whole Exome Sequencing (WES) data of a large South Indian family.MethodsWe recruited a large five generation of South Indian family (n=84) with positive family history of POAG. All study participants had comprehensive ocular evaluation (of the 84, 19 study subjects were diagnosed as POAG). Sanger sequencing of the candidate genes associated with POAG (MYOC, OPTN and TBK1) showed no genetic variation in the POAG affected family members. Therefore, we performed whole exome sequencing (WES) for 16 samples including (9 POAG and 7 unaffected controls) and the data was analysed using an in-house pipeline for prioritizing the pathogenic variants based on its segregation among the POAG individual.ResultsWe identified one novel and five low-frequency pathogenic variants with consistent co-segregation in all affected individuals. The variant c.G3719A in RPGR-interacting domain of RPGRIP1 that segregated heterozygously with the six POAG cases is distinct from variants causing photoreceptor dystrophies, reported to affect the RPGR protein complex signaling in primary cilia. The cilia in TM cells has been reported to mediate the intraocular pressure (IOP) sensation. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and likely pathogenic variant in the RPGR gene, suggesting that they may alter the RhoA activity essential for IOP regulationConclusionOur study supports that low-frequency pathogenic variants in multiple genes and pathways probably affect the pathogenesis of Primary Open Angle Glaucoma in the large South Indian family.

scholarly journals Identification of TP53BP2 as a Novel Candidate Gene for Primary Open Angle Glaucoma by Whole Exome Sequencing in a Large Multiplex Family

2017 ◽  
Vol 55 (2) ◽  
pp. 1387-1395 ◽  
Author(s):  
Shazia Micheal ◽  
Nicole T.M. Saksens ◽  
Barend F. Hogewind ◽  
Muhammad Imran Khan ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Open Angle ◽  
Multiplex Family ◽  
Whole Exome

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.

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