Leveraging ancestry to improve causal variant identification in exome sequencing for monogenic disorders.
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SUBMITTER: Brown R
PROVIDER: S-EPMC4795218 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectivesWhole exome sequencing (WES) has been widely used to detect genetic disorders in critically ill children. Relevant data are lacking in pediatric intensive care units (PICUs) of China. This study aimed to investigate the spectrum of monogenic disorders, the diagnostic yield and clinical utility of WES from a PICU in a large children's hospital of China.MethodsFrom July 2017 to February 2020, WES was performed in 169 critically ill children with suspected monogenic diseases in the PICU of Beijing Children's Hospital. The clinical features, human phenotype ontology (HPO) terms, and assessment of clinical impact were analyzed.ResultsThe media age of the enrolled children was 10.5 months (range, 1 month to 14.8 years). After WES, a total of 43 patients (25%) were diagnosed with monogenic disorders. The most common categories of diseases were metabolic disease (33%), neuromuscular disease (19%), and multiple deformities (14%). The diagnosis yield of children with "metabolism/homeostasis disorder" and "growth delay" or "ocular anomalies" was higher than that of children without these features. In addition, the diagnosis rate increased when more features were observed in children. The results of WES had an impact on the treatment for 30 cases (70%): (1) change of treatment (n = 11), (2) disease monitoring initiation (n = 18), (3) other systemic evaluation (n = 3), (4) family intervention (n = 2), and (5) rehabilitation and redirection of care toward palliative care (n = 12).ConclusionWES can be used as an effective diagnostic tool in the PICU of China and has an important impact on the treatment of patients with suspected monogenic conditions.
| S-EPMC8440967 | biostudies-literature
Project description:Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias.We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease.We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.
| S-EPMC4406825 | biostudies-literature
Project description:BackgroundDystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.MethodsFor this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.FindingsWe sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.InterpretationIn this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.FundingElse Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
| S-EPMC8246240 | biostudies-literature
Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
| S-EPMC4278636 | biostudies-literature
Project description:BackgroundMonogenic diseases are individually rare but collectively common, and are likely underdiagnosed.ObjectivesThe purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort.MethodsExomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease.ResultsIn total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals.ConclusionsOverall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.
| S-EPMC7428466 | biostudies-literature
Project description:As test costs decline, whole-exome sequencing (WES) has become increasingly used for clinical diagnosis, and now represents the primary alternative to gene panel testing for patients with a suspected genetic disorder. We sought to compare the diagnostic yield of singleton-WES with simulated application of commercial gene panels in children suspected of having a genetically heterogeneous condition. Recruitment, singleton-WES and phenotype-driven variant analysis was completed for 145 paediatric patients. At recruitment, clinicians were required to propose commercial gene panel tests as an alternative to WES and nominate a phenotype-driven candidate gene list. In WES-diagnosed children, three commercial options for each proposed panel were identified and evaluated for hypothetical diagnostic yield assuming 100% analytical sensitivity and specificity. We compared the price of WES with the least costly panel in WES-diagnosed children. In WES-undiagnosed children, we evaluated the exonic coverage of their phenotype-driven gene list using aggregate data. WES diagnoses were made in genes not included in at least one-of-three commercial panels in 42% of cases. Had a panel been selected instead, 23% of WES-diagnosed children would not have been diagnosed. In 26% of cases, the least costly panel option would have been more expensive than WES. Evaluation of WES coverage found that at the most stringent level of 20× coverage, the likelihood of missing a clinically relevant variant in a candidate gene list was maximally 8%. The broader coverage of WES makes it a superior alternative to gene panel testing at similar financial cost for children with suspected complex monogenic phenotypes.
| S-EPMC5945679 | biostudies-literature
Project description:BackgroundPremature ovarian failure (POF) is a highly heterogeneous disorder that occurs in 1% of women of reproductive age. Very few causative genes and variants contributing to POF have been detected, and the disease remains incompletely understood. In this study, we used whole exome sequencing (WES) to identify potential causal variants leading to POF.MethodsWES was conducted to identify variants in 34 Korean patients with POF, alongside 10 normal controls. Detected variants were filtered using a range of characterized bioinformatics analyses, and the machine learning tools, CADD and VEST, were used to predict pathogenic variants that could cause disease. VarSome was used for a comprehensive interpretation of the variants. Potential causal variants finally screened by these analyses were confirmed using Sanger sequencing.ResultsWe identified nine potential causative variants in genes previously associated with POF in 8 of 34 (24%) Korean patients by WES variant analysis. These potentially pathogenic variants included mutations in the MCM8, MCM9, and HFM1 genes, which are involved in homologous recombination, DNA repair, and meiosis, and are established as causing POF. Using a combination of CADD and VEST, 72 coding variants were also identified in 72 genes, including ADAMTSL1 and FER1L6, which have plausible functional links to POF.ConclusionsWES is a useful tool to detect genetic variants that cause POF. Accumulation and systematic management of data from a number of WES studies in specialized groups of patients with POF (family data, severe case populations) are needed to better comprehend the genetic landscape underlying POF.
| S-EPMC7590468 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a highly prevalent chronic autoimmune disease. However, genetic and environmental factors involved in RA pathogenesis are still remained largely unknown. To identify the genetic causal variants underlying pathogenesis and disease progression of RA patients, we undertook the first comprehensive whole-exome sequencing (WES) study in a total of 124 subjects including 58 RA cases and 66 healthy controls in Han Chinese population. We identified 378 novel genes that were enriched with deleterious variants in RA patients using a gene burden test. The further functional effects of associated genetic genes were classified and assessed, including 21 newly identified genes that were involved in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, focal adhesion and glycerophospholipid metabolism pathways relevant to RA pathogenesis. Moreover, six pathogenic variants were investigated and structural analysis predicted their potentially functional alteration by homology modeling. Importantly, five novel and rare homozygous variants (NCR3LG1, RAP1GAP, CHCHD5, HIPK2 and DIAPH2) were identified, which may exhibit more functional impact on RA pathogenesis. Notably, 7 genes involved in the olfactory transduction pathway were enriched and associated with RA disease progression. Therefore, we performed an efficient and powerful technique WES in Chinese RA patients and identified novel, rare and common disease causing genes that alter innate immunity pathways and contribute to the risk of RA. Findings in this study may provide potential diagnostic tools and therapeutic strategies for RA patients.
| S-EPMC5762310 | biostudies-literature
Project description:Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.
| S-EPMC3585308 | biostudies-literature
Project description:Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives.
| S-EPMC3675126 | biostudies-literature