Whole Exome Sequencing Analysis in AML with Normal Karyotype Not Harboring FLT3/ITD Mutation Reveals Novel Genetic Alterations.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2593-2593
Author(s):  
Il-Kwon Lee ◽  
Namshin Kim ◽  
Yeo-Kyeoung Kim ◽  
Dennis Dong Hwan Kim ◽  
Quang Trinh ◽  
...  
Keyword(s):  
Complete Remission ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Sequencing Analysis ◽  
Novel Mutations ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Custom Made

Abstract Abstract 2593 Background: NK-AML represents genetically heterogeneous group of disease. However genetic lesions affecting treatment outcome in patients with NK-AML are relatively unknown. Methods: The discovery cohort consists of 67 NK-AML patients in complete remission (median age: 49.2, ranges: 19–70) without FLT-3 mutations. Genomic DNA was extracted from enriched AML cells at diagnosis or control specimens obtained after complete remission. Whole exomes were captured using Agilent SureSelect and sequencing were performed by HiSeq2000 with 41∼89× coverage. Bioinformatics analysis and identification of somatic mutation has been done by series of software such as BWA, Picard, GATK, VarScan 2, and custom-made scripts. All the data has been re-checked by manual inspection. Validation has been done independent set of cohort (358 NK-AML patients, median age: 51, ranges: 15–85) with Sanger sequencing on highly mutated target sites. Results: Filtering against dbSNP and COSMIC database generated 485 genes with somatic and structural variations. Among them, 41 genes were detected in more than two patients. In addition to well-known 28 mutations, 13 novel mutations with different frequencies were identified including genes responsible for structural maintenance of chromosome (SMC1A, 6.0%) and tumor suppressor function (FAT1, 6.0%). Most common type of mutation was missense mutation (70.8%), and substantial fraction of mutation was splicing site mutations (3.8%). The hematological system development and hematologic function were most highly enriched by the Ingenuity Pathway Analysis (IPA) as expected. CIRCOS plot analysis showed similar co-occurring pattern of recurrent mutations with previous reports. Hierarchical clustering analysis divided into four different groups according to the number of harboring mutations. In network analysis four distinct subgroups were observed ranging 21 to 3 gene network. Conclusion: Using whole exome sequencing approach, a catalog of recurrent mutations was successfully defined in the patients with NK-AML without FLT3/ITD mutation. This candidate list of novel mutations should be tested further for therapeutic target and prognostic marker in the patients with NK-AML. Disclosures: No relevant conflicts of interest to declare.

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

Whole Exome Sequencing Reveals Spectrum of Gene Mutations in Pediatric AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 124-124
Author(s):  
Norio Shiba ◽  
Kenichi Yoshida ◽  
Yusuke Okuno ◽  
Yuichi Shiraishi ◽  
Yasunobu Nagata ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Conflicts Of Interest ◽  
Massively Parallel Sequencing ◽  
Gene Mutations ◽  
Pediatric Leukemia ◽  
Protein Coding ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Pediatric Aml

Abstract Abstract 124 Background Pediatric acute myeloid leukemia (AML) comprises ∼20% of pediatric leukemia, representing one of the major therapeutic challenges in pediatric oncology with the current overall survival remains to be ∼60%. As for the molecular pathogenesis of pediatric AML, it has been well established that gene fusions generated by recurrent chromosomal translocations, including t(15;17), t(8;21), inv(16) and t(9;11), play critical roles in leukemogenesis. However, they are not sufficient for leukemogenesis, indicating apparent need of additional genetic hits, and approximately 20% of pediatric AML cases lack any detectable chromosomal abnormalities (normal karyotype AML). Currently, a number of gene mutations have been implicated in the pathogenesis of both adult and pediatric AML, including mutations of RAS, KIT and FLT3, and more recently, a new class of mutational targets have been reported in adult AML, including CEBPA, NPM1, DNMT3A, IDH1/2, TET2 and EZH2. However, mutations of the latter class of gene targets seem to be rare in pediatric AML cases, whereas other abnormalities such as a NUP98-NSD1 fusion are barely found in adult cases, indicating the discrete pathogenesis between both AML at least in their subsets. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across the entire genomes or protein-coding sequences in human cancers at a single-nucleotide level, which could be successfully applied to the genetic analysis of pediatric AML to obtain a better understanding of its pathogenesis. Methods In order to reveal a complete registry of gene mutations and other genetic lesions, we performed whole exome sequencing of paired tumor-normal specimens from 23 pediatric AML cases using Illumina HiSeq 2000. Although incapable of detecting non-coding mutations and gene rearrangements, the whole-exome approach is a well-established strategy for obtaining comprehensive spectrum of protein-coding mutations. Recurrently mutated genes were further examined for mutations in an extended cohort of 200 pediatric AML samples, using deep sequencing, in which the prevalence and relative allele frequencies of mutations were investigated. Results Whole-exome sequencing of paired tumor-normal DNA from 23 patients were analyzed with a mean coverage of more than x120, and 90 % of the target sequences were analyzed at more than x20 depth on average. A total of 237 somatic mutations or 10.3 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in adult AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1, MLL3, BCOR, BCORL1, EZH2, and major cohesin components including XXX and ZZZ. On the other hand, several genes were newly identified in the current study, including BRAF, CUL2 and COL4A5, which were validated for the clinical significance in an extended cohort of 200 pediatric cases. Discussion Whole exome sequencing unmasked a complexity of gene mutations in pediatric AML genomes. Our results indicated that a subset of pediatric AML represents a discrete entity that could be discriminated from the adult counterpart, in terms of the spectrum of gene mutations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole Exome Sequencing of Relapsed Double-Mutated CEBPA Acute Myeloid Leukemia Identified Mutated KIT and WNT10A As a Potential Co-Mutation with Negative Impact on Prognosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5177-5177
Author(s):  
Chin-Hin NG ◽  
Alvin Yu-Jin Ng ◽  
Benedict Yan ◽  
Wee-Joo Chng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Beta Catenin ◽  
Novel Mutations ◽  
Whole Exome ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) with double-mutated CEBPA (dmCEBPA) occurred in about 10% of AML and it is usually associated with normal karyotype AML. It is classified as a favorable risk AML with an estimated 5 years overall survival in excess of 50%. Patients who achieved complete remission (CR) with induction chemotherapy will be consolidated with chemotherapy. Around 40% of the patients would suffer a relapse and required further salvage chemotherapy followed by allogeneic stem cell transplant. Co-mutations occurred frequently in dmCEBPA AML with TET2 being the most commonly co-mutated (34%) followed by GATA1 mutation (21%), WT1(13.7%), DNMT3a (9.6%), ASXL1 (9.5%), NRAS (8.4%) and other less common genes. Only TET2 mutation appeared to have negative impact on prognosis. In this study, we explore the relapse cases with Whole-Exome sequencing (WES) and compared with a control case (Chemo-responsive dmCEBPA AML who is in continuous complete remission (CCR)). We aimed to identify novel mutations not previously reported and with potential as new prognostic marker as well as therapeutic target for further exploration. Method: We identified 3 relapsed dmCEBPA AML cases from our leukemia cell bank and compared with a case of chemo-responsive dmCEBPA AML who is still in CCR at 8 years follow-up. Duration of prior CR for case #1, #2 and #3 were 10 months, 1 year 9 month and 1 year 10 months. WES was performed for all 4 cases. In each case, the variants were annotated using the IonReporter software and an additional customized script that annotates for variant population frequency, genotype-phenotype associations and computational missense prediction tools. Variants were filtered by removing all reference calls, intergenic variants and variants not present in the chemoresponsive case. Only exonic and non-synonymous variants were considered. Next, we look for variants with a phenotype-genotype association common with the AML phenotype by looking for variants with "Leukemia" terms listed in OMIM. In addition, in order to identify novel mutations not presently associated with AML, we identified variants that had a "Pathogenic" entry in ClinVar. Results: All 4 cases revealed the typical CEBPA mutants with VAF exceeding 40% except one with germline mutation. When compared with the chemo-responsive case, KIT was mutated in 2 out of 3 relapse cases. WNT10A was mutated in all 3 cases. The details of the mutated genes are presented in Table 1 (see below). WNT10A gene encodes for a secretory signaling protein in the WNT family of structurally related genes that are involved WNT-beta-catenin-TCF signaling pathway. WNT10A is strongly expressed in cell lines of promyelocytic leukemia. Beta-catenin, the downstream target of the WNT signaling pathway, is highly expressed in poor prognostic AML cells (Staal et al. Nature review Immun 2008). The Gly213 residue is highly evolutionary conserved in vertebrate with a PhyloP score of 9.8. Both missense variants Gly213Ser and Arg171Cys are computationally predicted be damaging (DANN score 0.99). However, these 2 variants are fairly common in the East Asian population (gnomAD_EAS MAF G213S 2.7% & R171C 1.5%). Both variants are ACMG guidelines classified as Variants of Unknown Significance (VUS). KIT gene encodes for the proto-oncogene c-kit. Mutations in c-kit are associated with mastocytosis and AML. Both variants occur within the kinase domain (exon 17) of KIT. Asp816Val variant has been linked to poorer prognosis and worse outcome on AML patients. Both missense variants are computationally predicted to be damaging (DANN score 0.99). Both Asp816Val and Asn822Lys are AMCG classified as Likely Pathogenic and VUS respectively. Conclusion: With stringent criteria of filtering in WES of relapsed dmCEBPA cases, when compared with the control, we found that KIT was mutated in 2 out of 3 cases, while WNT10A was mutated in all 3 cases. Though the sample number was small, these findings would warrant further evaluation in larger cohort of dmCEBPA AML and interrogation in pre-clinical model. Table 1. Disclosures No relevant conflicts of interest to declare.

Whole-Exome Sequencing Of Adult Philadephia-Negative Acute Lymphoblastic Leukemia From Diagnosis To Relapse After Allogeneic Hematopoietic Stem Cell Transplantation Reveals Clonal Evolution and Relapse-Associated Mutated Genes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 156-156
Author(s):  
Haowen Xiao ◽  
Yi Luo ◽  
Xiaoyu Lai ◽  
Jimin Shi ◽  
Yamin Tan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Sequencing Analysis ◽  
Hematopoietic Stem ◽  
Whole Exome ◽  
Matched Samples

Abstract Introduction Although steady progress of effective chemotherapy in childhood acute lymphoblastic leukemia (ALL) carried with exceeding 80% of individuals now cured, the majority of adult patients with ALL are not cured by chemotherapy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option. However, relapse remains the most leading cause of death after allo-HSCT. Adverse genetic alterations are generally accepted to be responsible for treatment failure and relapse. Several structural chromosomal alterations including rearrangement of the myeloid-lymphoid or mixed-lineage leukemia gene (MLL) and Philadelphia chromosome (Ph), have been mostly found in relapsed ALL. However, many Ph-negative (Ph-) ALL patients with normal karyotype , lacking known risk factors, also experienced relapse. The underlying pathologic determinants leading to relapse and prognostic markers in these cases remain poorly understood. More importantly, allo-HSCT is a distinct treatment option from tradtional chemotherapy and has 2 important forms to eliminate and select on malignant cells. The malignant cells that go on to causing relapse must initially survive ablation of chemotherapy before allo-HSCT and conditioning regimen in allo-HSCT. Then, after allo-HSCT, they must survive the effect of graft-versus- leukemia (GVL) reaction. Following this rationale, we hypothesized that there may be pivotal genetic causes confer leukemic cells a fitness advantage to undergo huge selective pressures and expand after allo-HSCT. To elucidate the genomic basis underlying relapse after allo-HSCT to aid to discover novel predictive biomarkers and identify therapeutic targets, we carried out the first whole-exome sequencing analysis in longitudinal matched samples from diagnosis to relapse after allo-HSCT in adult patients with the most common subtype of ALL, Ph- B-cell ALL (B-ALL). Methods Whole-exome sequencing was conducted for 9 genomic DNA samples from 3 relapsed cases with Ph- B-ALL (discovery cohort) at 3 specific time points including: diagnosis, complete remission (CR) after induction chemotherapy before allo-HSCT, relapse after allo-HSCT to discover candidate relapse-associated mutated genes. We identified putative somatic mutations by comparing each tumor ( diagnostic samples or relapsed samples) to normal (CR samples) from the same patient. To confirm candidate somatic gene mutations, screen relapse-associated gene mutations and define the frequency of somatic mutations identified by whole-exome sequencing analysis, we further carried out target genes whole coding regions sequencing in an ALL extended validation cohort including 58 adult Ph- B-ALL cases, where 27 patients experienced relapse at a median time of 6.5 (range 2-33) months after allo-HSCT and 31 patients did not relapse after allo-HSCT at a median follow-up for 34 (range 12–56) months. Results (1) We discovered novel associations of recurrently mutated genes (CREBBP, KRAS, PTPN21) with the pathogenesis of adult Ph- B-ALL relapse after allo-HSCT, which were mutated in at least two relapsed cases, but were not mutated in non- relapsed patients. (2) The generation of high-depth whole-exome sequencing data in longitudinal matched samples from diagnosis to relapse after allo-HSCT in initial 3 patients allowed us to directly assessed the evolution of somatic mutations. Our data suggested that in the progression of leukemia relapse after allo-HSCT, the relapse clone had a clear relationship to the diagnosis clone, either arising from a subclone already exsiting in the diagnostic tumor, or originating from a common preleukemic progenitor with the diagnosis clone. In the latter pattern, the relapse clone acquires new genetic alterations while retaining some but not all of the alterations found in the diagnostic tumor. In contrast, in some cases, leukemia recurrences afer allo-HSCT may be composed of second malignancies with completely distinct sets of mutations from the primary tumor. Conclusions Our study is the first to explore genetic basis of adult Ph- B-ALL from diagnosis to relapse after allo-HSCT over time, which will provide novel genetic biomarkers on risk “index” to improve individualized treatment intensification and intervention strategies, and potential therapeutic targets for Ph--ALL relapse after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis

Gut ◽  
2018 ◽  
Vol 68 (6) ◽  
pp. 1024-1033 ◽  
Author(s):  
Maolan Li ◽  
Fatao Liu ◽  
Fei Zhang ◽  
Weiping Zhou ◽  
Xiaoqing Jiang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ectopic Expression ◽  
Sequencing Analysis ◽  
Antibody Treatment ◽  
Whole Exome ◽  
Recurrent Mutations

ObjectivesPatients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations.DesignWe performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo.ResultsWES identified ERBB2 and ERBB3 mutations at a frequency of 7%–8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities.ConclusionsERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment.Trial registration numberNCT02442414;Pre-results.

scholarly journals Archiving of Somatic Novel Mutations Using Whole-Exome Sequencing in Pakistani Myeloid Leukemic Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5167-5167
Author(s):  
Abdul Rehman Khalil ◽  
Arshi Naz ◽  
Ikramdin Ujjan ◽  
Tahir S. Shamsi
Keyword(s):  
Gene Ontology ◽  
Acute Myeloid Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pathway Analysis ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
Whole Exome ◽  
Recurrent Mutations ◽  
Acute Myeloid

Introduction Acute myeloid leukemia (AML) is a highly malignant cancer of the bone marrow, clinically and genetically heterogenous clonal disease illustrated by the accumulation of acquired somatic genetic alterations in hematopoietic progenitor cells that modify normal mechanisms of self-renewal, proliferation and differentiation. AML cytogenetic studies provide important diagnostic and prognostic information for AML patients. However, approximately 50% of AML patients have a normal karyotype (NK- AML). Large number of causal mutations of AML has not yet been uncovered. Although disease etiology is still unknown after multiple OMIC's study were published. In this review an attempt is made to approach the subject in the light of currently available literature. Material and Methods Material and information of diagnosed cases of de novo AML (n=14) used after approval of Institutional Ethics Review Committee. Morphological subtypes of AML were classified according to WHO classification. A researcher used retrospective medical record review to obtain clinical, diagnostic data including disease status and blood chemistry and as well as archived genomic DNA of untreated cases. Mutational analysis was done to identify AML somatic mutations using the whole-exome sequencing. The library preparation along with the capture used the illumina TruSeq DNA Exome kit. NGS HS Kit -Proposed sequencing platform - illumina® NovaSeq 6000, 300 cycles -100X coverage - approx. 6Gb per sample. We explored the functional impact of the genes identified in the mutational analyses through an integrated Gene Ontology (GO) and pathway analysis. Results Majority of patients were 10 male with median age 40 range (23-60 years). AML with normal karyo type AML (NK-AML) were five included with maturation, without maturation and monocytic lineage. Significant somatic single nucleotide variants (SNVs) were identified and pathway analysis performed to determine frequently affected signaling pathways. We identified significant, novel recurrent mutations in MAML3 gene (8 patients). No significant novel gene identified in three abnormal karyo type AML (AK-AML). Five out of the 30 novel genes have previously been reported to be associated with other diseases. MAML3 showed statistical significance exclusively in NK-AML patients(n=5). A total of 700 genes identified 500 missense, 25 nonsense, 90 frameshift indels, and/or three stop codon deletions. Using the IntOGen platform, we identified MAP kinase, cell cycle, actin cytoskeleton regulation, PI3K-Akt signaling and other pathways in cancer as affected in the samples. Conclusion This data is the first of its kind from the Pakistani population.Specific patterns of genomic alterations may play an important role in sub types of morphological AML. Future studies to evaluate the usefulness of these genes in genetic testing for the early diagnosis and prognostic prediction of AML patients would be worthwhile. Keywords: Acute myeloid leukemia, Gene ontology, Pathway analysis, Somatic mutation, Subtype-specific mutation, Whole-exome sequencing Disclosures No relevant conflicts of interest to declare.

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 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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