102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 220-220
Author(s):  
Charuta Gavankar Furey ◽  
Jungmin Choi ◽  
Daniel Duran ◽  
Andrew T Timberlake ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
The United States ◽  
Congenital Hydrocephalus ◽  
Common Disease ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Abstract INTRODUCTION Congenital hydrocephalus (CH), with an estimated prevalence of 1 in 1000 births, is the most common disease treated by pediatric neurosurgeons, and exerts a tremendous burden on the United States health care budget, consuming over $2 billion annually. Paradoxically, CH treatments remain inadequate, crude, and primarily symptomatic, comprised largely of surgical shunts riddled with infectious and mechanical complications. Despite evidence that genetic factors play a major role in the pathogenesis of CH an estimated 40% of human CH has a genetic etiology our knowledge of specific CH-causing mutations and their pathogenic mechanisms remains primitive. Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies. However, traditional genetic approaches have been limited in their ability to identify causative CH genes because kindreds are rare, small in size, or appear to have sporadic inheritance patterns. Next-generation sequencing, and specifically whole exome sequencing (WES), can overcome these barriers to gene discovery. METHODS We performed whole-exome sequencing on DNA isolated from 130 patient-parent trios (affected patient and unaffected parents) and an additional 57 probands for a total of 187 CH patients with non-L1CAM primary CH. Exome-sequencing data from these 447 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH, and candidate mutations were subsequently confirmed by Sanger sequencing. RESULTS >Exome sequencing identified multiple novel and recurrent de novo and transmitted loss-of function gene mutations enriched in neurodevelopmental and ciliogenesis pathways. Binomial and case-control analyses confirmed exome-wide statistical significance of candidate genes, and functional modeling in Xenopus established gene causality. CONCLUSION These findings reveal novel disease-causing mutations in human CH, thereby providing new opportunities for improved prognostic assessment and non-invasive therapies.

scholarly journals Identifying Possible Candidate Factors Influencing the Penetrance of Heterozygous NFKB1 Loss of Function Mutations By Whole Exome Sequencing

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3706-3706
Author(s):  
Cyrill Schipp ◽  
Arndt Borkhardt ◽  
Polina Stepensky ◽  
Ute Fischer
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Bioinformatics Analyses ◽  
Factors Influencing ◽  
Whole Exome

Abstract Introduction The NFκB signaling pathway is a master regulator of immune and inflammatory responses. Recently we and other groups reported heterozygous NFKB1 loss-of-function mutations in patients with combined variable immunodeficiency (CVID) characterized by recurrent infections, autoimmunity and immunoglobulin deficiency. Pedigree analysis revealed incomplete penetrance of the disease causing mutation in 5 of the 6 analyzed families. While patients showed a severe phenotype including hypogammaglobulinemia, chronic infections and cytopenias, other carriers of the same mutation were unaffected except for slightly perturbed immunoglobulin levels indicating the existence of other factors influencing the penetrance of these mutations. Methods To identify genetic factors associated with complete penetrance of dominant NFKB1 mutations, whole exome sequencing was carried out using DNA extracted from blood samples derived from two patients and their families. Sequencing data of two patients and X unaffected carriers of the same NFKB1 mutations (p.R157X and p.I47fsX2) were then screened in silico for single nucleotide variations, small insertions and deletions present in modulators of immune responses in general and the NFκB pathway in particular, employing lists generated based on publicly available data on gene interactions (including e.g. data of the KEGG, and STRING databases). Results We detected no deleterious mutations in known modifier genes such as IL10, IL1B, IL6, CCR5, CCL5, RANTES, TGFB1 and others. But strikingly both patients harbored two polymorphisms (g.797C>A, Gly54Asp, Gly57Glu) in the Mannose Binding Lectin 2 (MBL2) gene that were previously reported as disease causing mutations in patients with primary immunodeficiency. These polymorphisms lead to reduced MBL2 expression and are linked with high susceptibility to infections. We hypothesize that low MBL2 expression in an NFKB1 haploinsufficient background may promote disease penetrance or increase the predisposition to infections. Conclusion Our combined next-generation sequencing and bioinformatics analyses approach identified MBL2 as an interesting candidate factor whose deficient expression may influence the penetrance of NFKB1 loss-of-function mutations. Further analysis of greater cohorts is needed to reinforce the role of MBL2 in the pathogenesis of NFKB1 haploinsufficiency. Disclosures No relevant conflicts of interest to declare.

Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy

2020 ◽  
Vol 51 (05) ◽  
pp. 368-372 ◽  
Author(s):  
Niklas Schwarz ◽  
Yvonne Weber ◽  
Hiltrud Muhle ◽  
Annika Rademacher ◽  
Simone Seiffert ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
West Syndrome ◽  
Network Effect ◽  
Seizure Outcome ◽  
Genetic Modifiers ◽  
Loss Of Function ◽  
Whole Exome ◽  
Increased Risk

AbstractPatients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype–phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.

scholarly journals Novel TNFAIP3 microdeletion in a girl with infantile-onset inflammatory bowel disease complicated by a severe perianal lesion

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Kosuke Taniguchi ◽  
Mikihiro Inoue ◽  
Katsuhiro Arai ◽  
Keiichi Uchida ◽  
Osuke Migita ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Bowel Disease ◽  
Early Onset ◽  
De Novo ◽  
Loss Of Function ◽  
Whole Exome ◽  
Inflammatory Bowel

AbstractA20 haploinsufficiency (HA20), a disease caused by loss-of-function TNFAIP3 mutations, manifests various autoinflammatory and/or autoimmune symptoms. Some cases of HA20 were initially diagnosed as very early onset inflammatory bowel disease (VEO-IBD). We performed whole-exome sequencing (WES) for a Japanese girl with infantile-onset IBD and a severe perianal lesion and detected a novel de novo 119 kb microdeletion containing only TNFAIP3 (arr[GRCh37] 6q23.3(138125829_138244816) × 1).

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.

scholarly journals Analysis workflow to assess de novo genetic variants from human whole-exome sequencing

2021 ◽  
Vol 2 (1) ◽  
pp. 100383
Author(s):  
Nicholas S. Diab ◽  
Spencer King ◽  
Weilai Dong ◽  
Garrett Allington ◽  
Amar Sheth ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
De Novo ◽  
Whole Exome ◽  
Analysis Workflow

scholarly journals Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 65
Author(s):  
Patricia Haug ◽  
Samuel Koller ◽  
Jordi Maggi ◽  
Elena Lang ◽  
Silke Feil ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Screening ◽  
De Novo ◽  
Efficient Tool ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Screening And Identification ◽  
High Throughput Dna Sequencing ◽  
New Mutations

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

scholarly journals A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Jennifer D. Hintzsche ◽  
William A. Robinson ◽  
Aik Choon Tan
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Disease Treatment ◽  
Computational Tools ◽  
Whole Exome ◽  
Data Production ◽  
Whole Exome Sequencing Data ◽  
Computationally Intensive ◽  
Generation Technology

Whole Exome Sequencing (WES) is the application of the next-generation technology to determine the variations in the exome and is becoming a standard approach in studying genetic variants in diseases. Understanding the exomes of individuals at single base resolution allows the identification of actionable mutations for disease treatment and management. WES technologies have shifted the bottleneck in experimental data production to computationally intensive informatics-based data analysis. Novel computational tools and methods have been developed to analyze and interpret WES data. Here, we review some of the current tools that are being used to analyze WES data. These tools range from the alignment of raw sequencing reads all the way to linking variants to actionable therapeutics. Strengths and weaknesses of each tool are discussed for the purpose of helping researchers make more informative decisions on selecting the best tools to analyze their WES data.

Screening of Candidate Pathogenic Genes for Spontaneous Abortion using Whole Exome Sequencing

2021 ◽  
Vol 24 ◽  
Author(s):  
Qingwen Zhu ◽  
Yiwen Zhou ◽  
Jiayi Ding ◽  
Li Chen ◽  
Jia Liu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spontaneous Abortion ◽  
Gene Fusion ◽  
High Throughput Sequencing ◽  
Kegg Pathway ◽  
Novel Mutation ◽  
Common Disease ◽  
Pathogenic Genes ◽  
Whole Exome

Background: Spontaneous abortion is a common disease in obstetrics and reproduction. Objective: This study aimed to screen candidate pathogenic genes for spontaneous abortion using whole-exome sequencing. Methods: Genomic DNA was extracted from abortion tissues of spontaneous abortion patients and sequenced using the Illumina HiSeq2500 high-throughput sequencing platform. Whole exome sequencing was performed to select harmful mutations, including SNP and insertion and deletion sites, associated with spontaneous abortion. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and gene fusion analyses were performed. MUC3A and PDE4DIP were two novel mutation genes that were screened and verified by PCR in abortion tissues of patients. Results: A total of 83,633 SNPs and 13,635 Indel mutations were detected, of which 29172 SNPs and 3093 Indels were screened as harmful mutations. The 7 GO-BP, 4 GO-CC, 9 GO-MF progress, and 3 KEGG pathways were enriched in GO and KEGG pathway analyses. A total of 746 gene fusion mutations were obtained, involving 492 genes. MUC3A and PDE4DIP were used for PCR verification because of their high number of mutation sites in all samples. Conclusion: There are extensive SNPs and Indel mutations in the genome of spontaneous abortion tissues, and the effect of these gene mutations on spontaneous abortion needs further experimental verification.

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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