scholarly journals SUN-721 Implementation of Whole Exome Sequencing for Clinical Diagnostics: A Prospective Busan Kyung-Sang Regional Co-Work Team Experience

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jeong Eun Lee ◽  
WooYeong Chung ◽  
BoLyun Lee ◽  
SooHyun Ku ◽  
Ga Won Jeon ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorder ◽  
Genetic Diseases ◽  
Clinical Diagnostics ◽  
Buccal Swab ◽  
Variant Interpretation ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Purpose: Next Generation Sequencing (NGS) technology is a highthroughput method for genome sequencing which assists clinicians with diagnosis of patients with suspected genetic disorders. This study was to investigate diagnostic yield and clinical utility of whole exome sequencing prospectively in the rare genetic diseases. Method: WES was performed a total of 178 patients with suspected genetic disorder. Buccal swab samples were collected from the patients to extract genomic DNA. WES and variant interpretation was conducted in 3 Billion Inc (Seoul, Republic of Korea), based on their own software. Patients’ phenotype was interpreted by clinical geneticists. Results: WES reported 117 variants (66.7%). According to the ACMG/AMP guidelines, there were 25 pathogenic variants (14%), 37 likely pathogenic variants (32%), and 55 VUS (31%). Among the 117 patients who detected variants, genotype-phenotype correlation was analyzed and resulted that 44 (38%) were found to be apparently causal mutation of the disease, 37 (32%) were not considered the cause of the disease, and 36 (31%) were withheld judgement. Of the VUS variants, 13% were likely to be the causal variants of the disease considering phenotype of patients. Conclusion: This study showed 38% of diagnostic yield in patients with unidentified genetic condition by using prospective WES based on automating variant interpretation system. In the diagnosis of rare genetic disease, we identified the need for a multi-disciplinary team to select appropriate subjects and interpret the clinical significance of the found genetic variants.

scholarly journals B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

2019 ◽  
Vol 46 (s1) ◽  
pp. S11
Author(s):  
L Gauquelin ◽  
T Hartley ◽  
M Tarnopolsky ◽  
DA Dyment ◽  
B Brais ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Cerebellar Atrophy ◽  
Clinical Findings ◽  
Disease Genes ◽  
Pathogenic Variants ◽  
Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

scholarly journals Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Elias L. Salfati ◽  
Emily G. Spencer ◽  
Sarah E. Topol ◽  
Evan D. Muse ◽  
Manuel Rueda ◽  
...  
Keyword(s):  
Sudden Death ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Diagnostic ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

scholarly journals Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia

2020 ◽  
Vol 6 (4) ◽  
pp. 00213-2020
Author(s):  
Alex Gileles-Hillel ◽  
Hagar Mor-Shaked ◽  
David Shoseyov ◽  
Joel Reiter ◽  
Reuven Tsabari ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Ciliary Dyskinesia ◽  
Diagnostic Yield ◽  
Characteristic Curve ◽  
Transmission Electron Microscopy Analysis ◽  
Alternative Diagnosis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Ciliary Dyskinesia

The diagnosis of primary ciliary dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified.To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene.Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in 11 known PCD-causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the receiver operating characteristic curve (AUC) 0.75, 95% CI 0.60–0.90). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97, 95% CI 0.93–1). Finally, WES established an alternative diagnosis in four patients.In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.

scholarly journals Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

2019 ◽  
Author(s):  
Go Hun Seo ◽  
Taeho Kim ◽  
Jung-young Park ◽  
Jungsul Lee ◽  
Sehwan Kim ◽  
...  
Keyword(s):  
Family Member ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Whole Exome ◽  
Interpretation System ◽  
Automated Interpretation ◽  
Age Range

AbstractPurposeEVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders.MethodsDNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to WES. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments.ResultsThe average number of overlapping organ categories per patient was 4.5 ± 5.0. EVIDENCE reported a total 244 variants in 215 (65.1%) of the 330 probands. After clinical reassessment and/or family member testing, 196 variants were identified in 171 probands (51.8%), including 115 novel variants. These variants were confirmed as being responsible for 146 genetic disorders. One hundred-seven (54.6%) of the 196 variants were categorized as pathogenic or likely pathogenic before, and 146 (74.6%) after, clinical assessment and/or family member testing. Factors associated with a variant being confirmed as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores between that variant and a patient’s phenotype.ConclusionThis new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 51% improvement in diagnostic yield.

scholarly journals Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hosneara Akter ◽  
Mohammad Shahnoor Hossain ◽  
Nushrat Jahan Dity ◽  
Md. Atikur Rahaman ◽  
K. M. Furkan Uddin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diseases ◽  
Leigh Syndrome ◽  
Genetic Profile ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Rare Genetic Diseases ◽  
Compound Heterozygous Variants

AbstractCollectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet–Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.

scholarly journals Novel Pathogenic Variant in the Cys110 Residue: A Genotype–Phenotype Report of a Patient with Norrie Disease

2019 ◽  
Vol 09 (02) ◽  
pp. 142-144
Author(s):  
Jaspreet Garcha ◽  
Angita Jain ◽  
Herjot Atwal ◽  
Pavalan Sevlam ◽  
Paldeep S. Atwal
Keyword(s):  
Retinal Detachment ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Phenotype ◽  
Hot Spot ◽  
Genetic Disorder ◽  
Male Infant ◽  
Norrie Disease ◽  
Pathogenic Variants ◽  
Whole Exome

AbstractNorrie disease is an X-linked genetic disorder caused by pathogenic mutations in the NDP. Here, we describe the clinical phenotype and genotype in a 19-week-old male infant with bilateral retinal detachment. Whole exome sequencing using available commercial methods on the proband revealed a hemizygous substitution in exon 3 of NDP, which suggests the etiology behind retinal detachment. This report not only adds to the expanding mutational spectrum of NDP-related retinopathies but also highlights the recurrence of pathogenic variants in the Cys110 residue, adding additional evidence to this residue as a potential mutational hot spot.

scholarly journals The utility of whole exome sequencing in diagnosing pediatric neurological disorders

2020 ◽  
Vol 23 (2) ◽  
pp. 17-24
Author(s):  
OY Muthaffar
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neurological Disorders ◽  
Diagnostic Yield ◽  
Wide Spectrum ◽  
Retrospective Chart Review ◽  
Signs And Symptoms ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Tertiary Center

Abstract Pediatric neurological disorders have a wide spectrum of clinical presentations and can be challenging to diagnose. Whole exome sequencing (WES) is increasingly becoming an integral diagnostic tool in medicine. It is cost-effective and has high diagnostic yield, especially in consanguineous populations. This study aims to review WES results and its value in diagnosing neurological disorders. A retrospective chart review was performed for WES results between the period of January 2018 to November 2019. Whole exome sequencing was requested for children with unexplained neurological signs and symptoms such as epilepsy, developmental delay, visual impairment, spasticity, hypotonia and magnetic resonance imaging (MRI) brain changes. It was conducted for children in a pediatric neurology clinic of a tertiary center at Jeddah, Saudi Arabia. Twenty-six children with undiagnosed neurological conditions were identified and underwent WES diagnosis. Nineteen patients (73.0%) of the cohort were diagnosed with pathogenic variants, likely pathogenic variants or variants of unknown significance (VUS). Consanguinity was positive in 18 families of the cohort (69.0%). Seven patients showed homozygous mutations. Five patients had heterozygous mutations. There were six patients with VUS and six patients had negative WES results. Whole exome sequencing showed a high diagnostic rate in this group of children with variable neurological disorders.

Genetic landscape of congenital disorders in patients from Southeast Asia: results from sequencing using a gene panel for Mendelian phenotypes

2020 ◽  
Vol 106 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Heming Wei ◽  
Angeline Lai ◽  
Ee Shien Tan ◽  
Mark Jean Aan Koh ◽  
Ivy Ng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Good Alternative ◽  
Gene Panel ◽  
Mendelian Disorders ◽  
Large Gene ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveTo test the utility and diagnostic yield of a medical-exome gene panel for identifying pathogenic variants in Mendelian disorders.MethodsNext-generation sequencing was performed with the TruSight One gene panel (targeting 4813 genes) followed by MiSeq sequencing on 216 patients who presented with suspected genetic disorders as assessed by their attending physicians.ResultsThere were 56 pathogenic and 36 likely pathogenic variants across 57 genes identified in 87 patients. Causal mutations were more likely to be truncating and from patients with a prior clinical diagnosis. Another 18 promising variants need further evaluation for more evidence to meet the requirement for potential upgrade to pathogenic. Forty-five of the 92 clinically significant variants were novel.ConclusionThe 40.3% positive yield compares favourably with similar studies using either this panel or whole exome sequencing, demonstrating that large gene panels could be a good alternative to whole exome sequencing for quick genetic confirmation of Mendelian disorders.

scholarly journals Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Peng ◽  
Shuting Yang ◽  
Xiaoliang Huang ◽  
Jialun Pang ◽  
Jing Liu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Recurrence Risk ◽  
Snp Analysis ◽  
Sequencing Analysis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Uncertain Significance

Background: Skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders that primarily affect bone and cartilage. This study aims to identify the genetic causes for fetal SDs, and evaluates the diagnostic yield of prenatal whole-exome sequencing (WES) for this disorder.Methods: WES was performed on 38 fetuses with sonographically identified SDs and normal results of karyotype and single nucleotide polymorphism (SNP) analysis. Candidate variants were selected by bioinformatics analysis, and verified by Sanger sequencing.Results: WES revealed pathogenic or likely pathogenic variants associated with SDs in 65.79% (25/38) of fetuses, variants of uncertain significance (VUS) in SDs-related genes in 10.53% (4/38) cases, and incidental findings in 31.58% (12/38) fetuses. The SDs-associated variants identified in the present study affected 10 genes, and 35.71% (10/28) of the variants were novel.Conclusion: WES has a high diagnostic rate for prenatal SDs, which improves pregnancy management, prenatal counseling and recurrence risk assessment for future pregnancies. The newly identified variants expanded mutation spectrum of this disorder.

scholarly journals Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

2020 ◽  
Vol 9 (7) ◽  
pp. 2220
Author(s):  
Robert Śmigiel ◽  
Mateusz Biela ◽  
Krzysztof Szmyd ◽  
Michal Błoch ◽  
Elżbieta Szmida ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Tool ◽  
Diagnostic Yield ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Monogenic Disease ◽  
Whole Exome

Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5–14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.

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