Exome Sequencing for The Identification of Mendelian Disease Genes

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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Point of Care Exome Sequencing Reveals Allelic and Phenotypic Heterogeneity Underlying Mendelian disease in Qatar

Human Molecular Genetics ◽

10.1093/hmg/ddz134 ◽

2019 ◽

Cited By ~ 1

Author(s):

Khalid A Fakhro ◽

Amal Robay ◽

Juan L Rodrigues-Flores ◽

Jason G Mezey ◽

Alya A Al-Shakaki ◽

...

Keyword(s):

Exome Sequencing ◽

De Novo ◽

Point Of Care ◽

Middle Eastern ◽

Disease Genes ◽

Mendelian Disease ◽

Dramatic Improvement ◽

Clinical Expertise ◽

Variant Prioritization ◽

Founder Mutations

Abstract The effectiveness of next generation sequencing at solving genetic disease has motivated the rapid adoption of this technology into clinical practice around the world. In this study, we use whole exome sequencing (WES) to assess 48 patients with Mendelian disease from 30 serial families as part of the “Qatar Mendelian Disease pilot program” – a coordinated multi-center effort to build capacity and clinical expertise in genetic medicine in Qatar. By enrolling whole families (parents plus available siblings), we demonstrate significantly improved discriminatory power for candidate variant identification over trios for both de novo and recessive inheritance patterns. For the same index cases, we further demonstrate that even in the absence of families, variant prioritization is improved up to 8-fold when a modest set of population-matched controls is used vs large public databases, stressing the poor representation of Middle Eastern alleles in presently available databases. Our in-house pipeline identified candidate disease variants in 27 of 30 families (90%), 23 of which (85%) harbor novel pathogenic variants in known disease genes, pointing to significant allelic heterogeneity and founder mutations underlying Mendelian disease in the Middle East. For 6 of these families, the clinical presentation was only partially explained by the candidate gene, suggesting phenotypic expansion of known syndromes. Our pilot study demonstrates the utility of WES for Middle Eastern populations, the dramatic improvement in variant prioritization conferred by enrolling population-matched controls and/or enrolling additional unaffected siblings at the point-of-care, and 25 novel disease-causing alleles, relevant to newborn and premarital screening panels in regional populations.

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

Frontiers in Genetics ◽

10.3389/fgene.2020.601566 ◽

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.

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

10.1101/151225 ◽

2017 ◽

Cited By ~ 1

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.

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Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Journal of Dental Research ◽

10.1177/0022034517724149 ◽

2017 ◽

Vol 97 (1) ◽

pp. 49-59 ◽

Cited By ~ 16

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.

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Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2016-0333 ◽

2017 ◽

Vol 30 (4) ◽

Cited By ~ 6

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.

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Exome sequencing as a tool for Mendelian disease gene discovery

Nature Reviews Genetics ◽

10.1038/nrg3031 ◽

2011 ◽

Vol 12 (11) ◽

pp. 745-755 ◽

Cited By ~ 1130

Author(s):

Michael J. Bamshad ◽

Sarah B. Ng ◽

Abigail W. Bigham ◽

Holly K. Tabor ◽

Mary J. Emond ◽

...

Keyword(s):

Exome Sequencing ◽

Disease Gene ◽

Gene Discovery ◽

Mendelian Disease ◽

Disease Gene Discovery

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759 – Significant Variants in Monogenic Inflammatory Bowel Disease Genes Identified by Whole Exome Sequencing of 400 Paediatric Patients

Gastroenterology ◽

10.1016/s0016-5085(19)37187-2 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-157-S-158

Author(s):

James J. Ashton ◽

Enrico Mossotto ◽

Imogen Stafford ◽

Tracy Coelho ◽

Nadeem A. Afzal ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Disease Genes ◽

Paediatric Patients ◽

Whole Exome ◽

Inflammatory Bowel

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Data-driven modelling of mutational hotspots and in silico predictors in hypertrophic cardiomyopathy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106922 ◽

2020 ◽

pp. jmedgenet-2020-106922

Author(s):

Adam Waring ◽

Andrew Harper ◽

Silvia Salatino ◽

Christopher Kramer ◽

Stefan Neubauer ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

In Silico ◽

Synthetic Data ◽

Missense Variant ◽

Statistical Modelling ◽

Disease Genes ◽

Mendelian Disease ◽

Modelling Framework ◽

Mutational Hotspots ◽

Anderson Darling

BackgroundAlthough rare missense variants in Mendelian disease genes often cluster in specific regions of proteins, it is unclear how to consider this when evaluating the pathogenicity of a gene or variant. Here we introduce methods for gene association and variant interpretation that use this powerful signal.MethodsWe present statistical methods to detect missense variant clustering (BIN-test) combined with burden information (ClusterBurden). We introduce a flexible generalised additive modelling (GAM) framework to identify mutational hotspots using burden and clustering information (hotspot model) and supplemented by in silico predictors (hotspot+ model). The methods were applied to synthetic data and a case–control dataset, comprising 5338 hypertrophic cardiomyopathy patients and 125 748 population reference samples over 34 putative cardiomyopathy genes.ResultsIn simulations, the BIN-test was almost twice as powerful as the Anderson-Darling or Kolmogorov-Smirnov tests; ClusterBurden was computationally faster and more powerful than alternative position-informed methods. For 6/8 sarcomeric genes with strong clustering, Clusterburden showed enhanced power over burden-alone, equivalent to increasing the sample size by 50%. Hotspot+ models that combine burden, clustering and in silico predictors outperform generic pathogenicity predictors and effectively integrate ACMG criteria PM1 and PP3 to yield strong or moderate evidence of pathogenicity for 31.8% of examined variants of uncertain significance.ConclusionGAMs represent a unified statistical modelling framework to combine burden, clustering and functional information. Hotspot models can refine maps of regional burden and hotspot+ models can be powerful predictors of variant pathogenicity. The BIN-test is a fast powerful approach to detect missense variant clustering that when combined with burden information (ClusterBurden) may enhance disease-gene discovery.

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Exome sequencing study of 20 patients with high myopia

PeerJ ◽

10.7717/peerj.5552 ◽

2018 ◽

Vol 6 ◽

pp. e5552 ◽

Cited By ~ 2

Author(s):

Ling Wan ◽

Boling Deng ◽

Zhengzheng Wu ◽

Xiaoming Chen

Keyword(s):

Exome Sequencing ◽

Candidate Genes ◽

High Myopia ◽

Cellular Response ◽

Gene Mutations ◽

Enrichment Analysis ◽

Zinc Ion ◽

Ocular Disease ◽

Disease Genes ◽

Bioinformatics Analyses

Background High myopia is a common ocular disease worldwide. To expand our current understanding of the genetic basis of high myopia, we carried out a whole exome sequencing (WES) study to identify potential causal gene mutations. Methods A total of 20 individuals with high myopia were exome sequenced. A novel filtering strategy combining phenotypes and functional impact of variants was applied to identify candidate genes by multi-step bioinformatics analyses. Network and enrichment analysis were employed to examine the biological pathways involved in the candidate genes. Results In 16 out of 20 patients, we identified 20 potential pathogenic gene variants for high myopia. A total of 18 variants were located in myopia-associated chromosomal regions. In addition to the novel mutations found in five known myopia genes (ADAMTS18, CSMD1, P3H2, RPGR, and SLC39A5), we also identified pathogenic variants in seven ocular disease genes (ABCA4, CEP290, HSPG2, PCDH15, SAG, SEMA4A, and USH2A) as novel candidate genes. The biological processes associated with vision were significantly enriched in our candidate genes, including visual perception, photoreceptor cell maintenance, retinoid metabolic process, and cellular response to zinc ion starvation. Discussion Systematic mutation analysis of candidate genes was performed using WES data, functional interaction (FI) network, Gene Ontology and pathway enrichment. FI network analysis revealed important network modules and regulator linker genes (EP300, CTNNB1) potentially related to high myopia development. Our study expanded the list of candidate genes associated with high myopia, which increased the genetic screening performance and provided implications for future studies on the molecular genetics of myopia.

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