scholarly journals High Frequency Actionable Pathogenic Exome Mutations in an Average-Risk Cohort

2017 ◽  
Author(s):  
Shannon Rego ◽  
Orit Dagan-Rosenfeld ◽  
Wenyu Zhou ◽  
M. Reza Sailani ◽  
Patricia Limcaoco ◽  
...  
Keyword(s):  
General Population ◽  
Exome Sequencing ◽  
Health Management ◽  
Disease Risk ◽  
Mendelian Inheritance ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Average Risk ◽  
Pathogenic Variants ◽  
Actionable Findings

AbstractWhole exome sequencing (WES) is increasingly utilized in both clinical and non-clinical settings, but little is known about the utility of WES in healthy individuals. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study at Stanford University. We assessed exomes for rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We used American College of Medical Genetics (ACMG) guidelines were used for the classification of rare sequence variants, and additionally we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes, including 6 (9%) with mutations in genes not currently included in the ACMG’s list of 59 actionable genes. This number is higher than that reported in previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 60 participants (89%) had non-actionable findings identified including 57 who were found to be mutation carriers for recessive diseases and 21 who have increased Alzheimer’s disease risk due to heterozyg ous or homozygousAPOEe4 alleles (18 participants had both). These results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.

scholarly journals Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi−Bickel Syndrome

2021 ◽  
Vol 11 ◽  
Author(s):  
Maryam Eghbali ◽  
Kiyana Sadat Fatemi ◽  
Shadab Salehpour ◽  
Maryam Abiri ◽  
Hassan Saei ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Disease Genes ◽  
Carrier Status ◽  
Mendelian Disease ◽  
Pathogenic Variants ◽  
Glycogen Storage Diseases ◽  
Whole Exome

Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG’s list of 59 actionable genes. For the interpretation of the causative variants and the incidental/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G > C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known/expected pathogenic variants were detected in the ACMG’s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.

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 Exome Sequencing for The Identification of Mendelian Disease Genes

2015 ◽  
Vol 36 (4) ◽  
pp. 139-143
Author(s):  
Gulsum Kayman Kurekci ◽  
Pervin Dincer
Keyword(s):  
Exome Sequencing ◽  
Disease Genes ◽  
Mendelian Disease

scholarly journals A Bayesian method using sparse data to estimate penetrance of disease-associated genetic variants

2019 ◽  
Author(s):  
Brett M. Kroncke ◽  
Derek K. Smith ◽  
Andrew M. Glazer ◽  
Dan M. Roden ◽  
Jeffrey D. Blume
Keyword(s):  
Rare Variants ◽  
Disease Risk ◽  
Genomic Medicine ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Phenotypic Data ◽  
Prior Probabilities ◽  
Cardiac Gene ◽  
Risk Of Disease

AbstractPurposeA major challenge in genomic medicine is how to best predict risk of disease from rare variants discovered in Mendelian disease genes but with limited phenotypic data. We have recently used Bayesian methods to show that in vitro functional measurements and computational pathogenicity classification of variants in the cardiac gene SCN5A correlate with rare arrhythmia penetrance. We hypothesized that similar predictors could be used to impute variant-specific penetrance prior probabilities.MethodsFrom a review of 756 publications, we developed a pattern mixture algorithm, based on a Bayesian Beta-Binomial model, to generate SCN5A variant-specific penetrance priors for the heart arrhythmia Brugada syndrome (BrS).ResultsThe resulting priors correlate with mean BrS penetrance posteriors (cross validated R2= 0.41). SCN5A variant function and structural context provide the most information predictive of BrS penetrance. The resulting priors are interpretable as equivalent to the observation of affected and unaffected carriers.ConclusionsBayesian estimates of penetrance can efficiently integrate variant-specific data (e.g. functional, structural, and sequence) to accurately estimate disease risk attributable to individual variants. We suggest this formulation of penetrance is quantitative, probabilistic, and more precise than, but consistent with, discrete pathogenicity classification approaches.

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

scholarly journals Rare Genetic Variation Underlying Human Diseases and Traits: Results from 200,000 Individuals in the UK Biobank

2020 ◽  
Author(s):  
Sean J. Jurgens ◽  
Seung Hoan Choi ◽  
Valerie N. Morrill ◽  
Mark Chaffin ◽  
James P. Pirruccello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Variation ◽  
Exome Sequencing ◽  
Human Diseases ◽  
Disease Genes ◽  
Uk Biobank ◽  
Novel Genes ◽  
Pathogenic Variants ◽  
Rare Genetic Variation ◽  
The Uk

AbstractBackgroundMany human diseases are known to have a genetic contribution. While genome-wide studies have identified many disease-associated loci, it remains challenging to elucidate causal genes. In contrast, exome sequencing provides an opportunity to identify new disease genes and large-effect variants of clinical relevance. We therefore sought to determine the contribution of rare genetic variation in a curated set of human diseases and traits using a unique resource of 200,000 individuals with exome sequencing data from the UK Biobank.Methods and ResultsWe included 199,832 participants with a mean age of 68 at follow-up. Exome-wide gene-based tests were performed for 64 diseases and 23 quantitative traits using a mixed-effects model, testing rare loss-of-function and damaging missense variants. We identified 51 known and 23 novel associations with 26 diseases and traits at a false-discovery-rate of 1%. There was a striking risk associated with many Mendelian disease genes including: MYPBC3 with over a 100-fold increased odds of hypertrophic cardiomyopathy, PKD1 with a greater than 25-fold increased odds of chronic kidney disease, and BRCA2, BRCA1, ATM and PALB2 with 3 to 10-fold increased odds of breast cancer. Notable novel findings included an association between GIGYF1 and type 2 diabetes (OR 5.6, P=5.35×10−8), elevated blood glucose, and lower insulin-like-growth-factor-1 levels. Rare variants in CCAR2 were also associated with diabetes risk (OR 13, P=8.5×10−8), while COL9A3 was associated with cataract (OR 3.4, P=6.7×10−8). Notable associations for blood lipids and hypercholesterolemia included NR1H3, RRBP1, GIGYF1, SCGN, APH1A, PDE3B and ANGPTL8. A number of novel genes were associated with height, including DTL, PIEZO1, SCUBE3, PAPPA and ADAMTS6, while BSN was associated with body-mass-index. We further assessed putatively pathogenic variants in known Mendelian cardiovascular disease genes and found that between 1.3 and 2.3% of the population carried likely pathogenic variants in known cardiomyopathy, arrhythmia or hypercholesterolemia genes.ConclusionsLarge-scale population sequencing identifies known and novel genes harboring high-impact variation for human traits and diseases. A number of novel findings, including GIGYF1,represent interesting potential therapeutic targets. Exome sequencing at scale can identify a meaningful proportion of the population that carries a pathogenic variant underlying cardiovascular disease.

scholarly journals Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study

Circulation ◽  
2021 ◽  
Author(s):  
Andrew M Glazer ◽  
Giovanni E. Davogustto ◽  
Christian M. Shaffer ◽  
Carlos G Vanoye ◽  
Reshma R. Desai ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Disease Risk ◽  
Large Population ◽  
Hek293 Cells ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Functional Evaluation ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability. Methods: The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.

scholarly journals Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

2018 ◽  
Vol 4 (1) ◽  
pp. e212 ◽  
Author(s):  
Gloria T. Haskell ◽  
Michael C. Adams ◽  
Zheng Fan ◽  
Krunal Amin ◽  
Roberto J. Guzman Badillo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Gene List ◽  
Disease Genes ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Prior Testing ◽  
Genome Scale

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

scholarly journals Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

2018 ◽  
Author(s):  
Suhas Ganesh ◽  
Ahmed P Husayn ◽  
Ravi Kumar Nadella ◽  
Ravi Prabhakar More ◽  
Manasa Sheshadri ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Exome Sequencing ◽  
Rare Variants ◽  
Association Studies ◽  
Mental Illnesses ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Genome Wide Association Studies ◽  
Complex Disorders ◽  
Family Based

AbstractIntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.MethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.ResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.ConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

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