scholarly journals Case Report: Exome Sequencing Identified Variants in Three Candidate Genes From Two Families With Hearing Loss, Onychodystrophy, and Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuan Li ◽  
Jianjun Xiong ◽  
Yi Zhang ◽  
Lin Xu ◽  
Jianyun Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
De Novo ◽  
Sequencing Analysis ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
Phenotype Analysis ◽  
Causal Allele ◽  
Β Sheet

A cohort of 542 individuals in 166 families with congenital hearing loss was recruited for whole-exome sequencing analysis. Here, we report the identification of three variants in five affected individuals in two unrelated families. In family 1, a nonsense mutation (c.1516C>T, p.R506*) in the ATP6V1B2 gene, a known causal allele for dominant deafness-onychodystrophy (DDOD), was identified in the mother and son with DDOD. However, a novel heterozygous variant (c.1590T>G, p.D530E) in TJP2, a known causal gene for hearing-loss, was also detected in the patients. In family 2, the same mutation (c.1516C>T, p.R506*) of ATP6V1B2 was detected from the father and daughter with DDOD. Furthermore, a novel heterozygous variant (c.733A>G, p.M245V) in the KIF11 gene was identified from the spouse with sensorineural hearing-loss and epilepsy. Notably, genotype-phenotype analysis of KIF11-associated disorders revealed that the p.M245V and two reported hearing-loss-associated variants (p.S235C and p.H244Y) are all mapped to a single β-sheet (Ser235∼M245) in the kinesin motor domain. Together, this is the first demonstration that ATP6V1B2-caused DDOD is an autosomal dominant genetic disease, compared to previous cases with de novo mutation. Our findings expand the variant spectrum of hearing-loss-associated genes and provide new insights on understanding of hearing-loss candidate genes ATP6V1B2, TJP2, and KIF11.

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.

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.

scholarly journals O2-10-02: WHOLE EXOME SEQUENCING ANALYSIS IN EARLY ONSET ALZHEIMER REVEALS NOVEL CANDIDATE GENES

2019 ◽  
Vol 15 ◽  
pp. P564-P564
Author(s):  
Victoria Fernandez ◽  
Dalton Huey ◽  
John P. Budde ◽  
Fabiana H.G. Farias ◽  
Oscar Harari ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Sequencing Analysis ◽  
Whole Exome

scholarly journals Next Generation Exome Sequencing of Pediatric Asthma Identifies Rare and Novel Variants in Candidate Genes

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Neda M. Bogari ◽  
Amr A. Amin ◽  
Husni H. Rayes ◽  
Ahmed Abdelmotelb ◽  
Mohiuddin M. Taher ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Association Studies ◽  
Severe Disease ◽  
Pediatric Asthma ◽  
Sequencing Analysis ◽  
Whole Exome ◽  
Novel Variants ◽  
The Impact

Multiple genes have been implicated to have a role in asthma predisposition by association studies. Pediatric patients often manifest a more extensive form of this disease and a particularly severe disease course. It is likely that genetic predisposition could play a more substantial role in this group. This study is aimed at identifying the spectrum of rare and novel variation in known pediatric asthma susceptibility genes using whole exome sequencing analysis in nine individual cases of childhood onset allergic asthma. DNA samples from the nine children with a history of bronchial asthma diagnosis underwent whole exome sequencing on Ion Proton. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. The analysis showed 21 variants in the subjects, 13 had been previously identified, and 8 were novel. Also, among of which, nineteen were nonsynonymous and 2 were nonsense. With regard to the novel variants, the 2 nonsynonymous variants in the PRKG1 gene (PRKG1: p.C519W and PRKG1: p.G520W) were presented in 4 cases, and a nonsynonymous variant in the MAVS gene (MAVS: p.A45V) was identified in 3 cases. The variants we found in this study will enrich the variant spectrum and build up the database in the Saudi population. Novel eight variants were identified in the study which provides more evidence in the genetic susceptibility in asthma among Saudi children, providing a genetic screening map for the molecular genetic determinants of allergic disease in Saudi children, with the goal of reducing the impact of chronic diseases on the health and the economy. We believe that the advanced specified statistical filtration/annotation programs used in this study succeeded to release such results in a preliminary study, exploring the genetic map of that disease in Saudi children.

scholarly journals Deleterious genetic variants in NOTCH1 are a major contributor to the incidence of non-syndromic Tetralogy of Fallot

2018 ◽  
Author(s):  
Donna J. Page ◽  
Matthieu J. Miossec ◽  
Simon G. Williams ◽  
Elisavet Fotiou ◽  
Richard M. Monaghan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Tetralogy Of Fallot ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
De Novo ◽  
Functional Domain ◽  
Functional Evaluation ◽  
Missense Variants ◽  
Whole Exome

AbstractAimsFamilial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD) phenotype. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. Here, we use whole exome sequencing to assess the prevalence of rare, potentially deleterious variants in candidate genes previously associated with both syndromic and non-syndromic TOF, in the largest cohort of non-syndromic TOF patients reported to date.Methods & Results829 non-syndromic TOF patients underwent whole exome sequencing. A systematic review of the literature was conducted which revealed 77 genes in which mutations had been reported in patients with TOF. The presence of rare, deleterious variants in the 77 candidate genes was determined, defined by a minor allele frequency of ≤ 0.001 and scaled combined annotation-dependent depletion (CADD) score of ≥ 20. We found a clustering of heterozygous rare, deleterious variants in NOTCH1 (P=1.89E-15), DOCK6 (P=2.93E-07), MYOM2 (P= 7.35E-05), TTC37 (P=0.016), MESP1 (P=0.024) and TBX1 (P=0.039), after correcting for multiple testing. NOTCH1 was most frequently found to harbour deleterious variants. Changes were observed in 49 patients (6%; 95% confidence interval [CI]: 4.5% - 7.8%) and included six truncating/frameshift variants and forty missense variants. Sanger sequencing of the unaffected parents of thirteen cases identified five de novo variants. Variants were not confined to a single functional domain of the NOTCH1 protein but significant clustering of variants was evident in the EGF-like repeats (P=0.018). Three NOTCH1 missense variants (p.G200R, p.C607Y and de novo p.N1875S) were subjected to functional evaluation and showed a reduction in Jagged1 ligand-induced NOTCH signalling. p.C607Y, which exhibited the most significant reduction in signalling, also perturbed S1 cleavage of the NOTCH1 receptor in the Golgi.ConclusionThe NOTCH1 locus is a frequent site of genetic variants predisposing to non-syndromic TOF with 6% of patients exhibiting rare, deleterious variants. Our data supports the polygenic origin of TOF and suggests larger studies may identify additional loci.

scholarly journals Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample

2019 ◽  
Vol 70 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Jian Jiao ◽  
Manxue Zhang ◽  
Pingyuan Yang ◽  
Yan Huang ◽  
Xiao Hu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Analysis Tool ◽  
Whole Exome

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. Whole-exome sequencing studies have shown that de novo single-nucleotide variations (SNVs) play an important role in sporadic ASD. The present study aimed to search for de novo SNVs using whole-exome sequencing in 59 unrelated Chinese ASD sporadic trios, and found 24 genes (including five reported ASD candidate genes CACNA1D, ACHE, YY1, TTN, and FBXO11) with de novo harmful SNVs. Five genes (CACNA1D, JAK2, ACHE, MAPK7, and PRKAG2) classified as “medium-confidence” genes were found to be related to ASD using the Phenolyzer gene analysis tool, which predicts the correlation between the candidate genes and the ASD phenotype. De novo SNVs in JAK2, MAPK7, and PRKAG2 were first found in ASD. Both JAK2 and MAPK7 were involved in the regulation of the MAPK signaling pathway. Gene co-expression and inter-gene interaction networks were constructed and gene expression data in different brain regions were further extracted, revealing that JAK2 and MAPK7 genes were associated with certain previously reported ASD genes and played an important role in early brain development. The findings of this study suggest that the aforementioned five reported ASD genes and JAK2 and MAPK7 may be related to ASD susceptibility. Further investigations of expression studies in cellular and animal models are needed to explore the mechanism underlying the involvement of JAK2 and MAPK7 in ASD.

scholarly journals Whole-exome sequencing as a powerful tool for identifying genetic causes in a patient with POLG-related disorders and phenylketonuria

2019 ◽  
Vol 47 (3) ◽  
pp. 1387-1394 ◽  
Author(s):  
Lin Li ◽  
Jin-Qi Zhao ◽  
Chengrong Wang ◽  
Nan Yang ◽  
Li-Fei Gong ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mental Retardation ◽  
Liver Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Genetic Causes ◽  
Whole Exome ◽  
Compound Heterozygous Mutations

Objective This study’s aim was to identify the genetic causes in a patient with phenylketonuria and hearing loss, liver disease, developmental and mental retardation, hypotonia, and external ophthalmoplegia. Methods Whole-exome sequencing and Sanger sequencing analysis were used to determine the genetic causes of manifestations in a young boy with hearing loss, liver disease, develop-mental and mental retardation, hypotonia, and external ophthalmoplegia. Results We found that the child harbored polymerase gamma ( POLG) compound heterozygous mutations, c.2617G>A (p.E873K) and c.3550G>A (p.D1184N), and phenylalanine hydroxylase ( PAH) compound heterozygous mutations, c.721C>T (p.R241C) and c.728G>A (p.R243Q). Among them, the POLG p.E873K mutation is a novel mutation and is not present in the Exome Aggregation Consortium database, Genome Aggregation database, and 1000 Genomes database. The two heterozygous mutations were each inherited from both of the child’s parents. This finding suggested that the phenotype and the genotype were segregated. Conclusion Using whole-exome sequencing, we not only identified PAH mutations causing phenylketonuria, but also identified the genetic cause of the mitochondrial disease and found a novel POLG mutation. Our findings could be useful in helping future parents obtain healthy embryos through assisted reproductive technology.

scholarly journals NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Xu ◽  
Yong-Biao Zhang ◽  
Li-Jun Liang ◽  
Jia-Li Tian ◽  
Jin-Ming Lin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Sanger Sequencing ◽  
Conformational Stability ◽  
Sequencing Analysis ◽  
Large Pedigree ◽  
Whole Exome ◽  
Variant Filtering ◽  
Genetic Contributions

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

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