ClinLabGeneticist: a tool for clinical management of genetic variants from whole exome sequencing in clinical genetic laboratories

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

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Identification of rare genetic variants in Juvenile Idiopathic Arthritis using whole exome sequencing

Pediatric Rheumatology ◽

10.1186/1546-0096-13-s1-p144 ◽

2015 ◽

Vol 13 (S1) ◽

Author(s):

E Sanchez ◽

S Grandemange ◽

F Tran Mau-Them ◽

P Louis-Plence ◽

A Carbasse ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Whole Exome ◽

Rare Genetic Variants

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Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd9010002 ◽

2021 ◽

Vol 9 (1) ◽

pp. 2

Author(s):

Laura Pezzoli ◽

Lidia Pezzani ◽

Ezio Bonanomi ◽

Chiara Marrone ◽

Agnese Scatigno ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Molecular Diagnosis ◽

Clinical Management ◽

Genetic Diagnosis ◽

Family Management ◽

Whole Exome ◽

Time To Diagnosis ◽

The Mean ◽

Mean Time

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

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Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Circulation ◽

10.1161/circ.132.suppl_3.16468 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Stephanie M Ware ◽

Steven E Lipshultz ◽

Steven D Colan ◽

Ling Shi ◽

Charles E Canter ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Risk Stratification ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Genetic ◽

Clinical Genetic Testing ◽

Whole Exome ◽

Pediatric Cardiomyopathy ◽

History Of

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification.

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Whole-exome sequencing of non-metastatic anal squamous cell carcinoma: a prognostic genetic variants analysis

Annals of Oncology ◽

10.1093/annonc/mdz155.162 ◽

2019 ◽

Vol 30 ◽

pp. iv44

Author(s):

I. Ghanem ◽

L. Trilla ◽

A. Gámez ◽

M. Mendiola ◽

J. Maurel ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Squamous Cell ◽

Genetic Variants ◽

Anal Squamous Cell Carcinoma ◽

Whole Exome

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Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Haematologica ◽

10.3324/haematol.2016.146316 ◽

2016 ◽

Vol 101 (10) ◽

pp. 1170-1179 ◽

Cited By ~ 63

Author(s):

B. Johnson ◽

G. C. Lowe ◽

J. Futterer ◽

M. Lordkipanidze ◽

D. MacDonald ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Whole Exome ◽

Inherited Thrombocytopenia

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Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

10.1101/060319 ◽

2016 ◽

Cited By ~ 1

Author(s):

M Córdoba ◽

SA Rodriguez-Quiroga ◽

PA Vega ◽

H Amartino ◽

C Vázquez-Dusefante ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Low Income ◽

Clinical Management ◽

Diagnostic Yield ◽

Genetic Disorders ◽

Potential Cost ◽

Low Income Country ◽

Whole Exome ◽

Neurogenetic Disorders

ABSTRACTClinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a “diagnostic odyssey” for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country. Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to WES which added up to a median cost of $3537.6 ($2892 to $5084) for the diagnostic odysseys experienced by our cohort.

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Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

10.1101/472803 ◽

2018 ◽

Author(s):

Youngha Lee ◽

Jin Sook Lee ◽

Soo Yeon Kim ◽

Jaeso Cho ◽

Yongjin Yoo ◽

...

Keyword(s):

Genetic Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Variants ◽

Neurodevelopmental Disorders ◽

Pediatric Patients ◽

Medical System ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants

AbstractImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).ObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.Design, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Children’s Hospital.ExposuresWES of patients and parents and subsequent evaluation of genetic variants.Main outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.ResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.Conclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.Key pointsQuestionWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?FindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.MeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

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OP64 Implementation Of Whole Exome Sequencing For Rare Diseases

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462319001259 ◽

2019 ◽

Vol 35 (S1) ◽

pp. 16-16

Author(s):

Paul Fennessy ◽

Marianne Griffin

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Management ◽

Evidence Based ◽

Traffic Light ◽

Eligibility Criteria ◽

Hub And Spoke ◽

Clinical Model ◽

Whole Exome ◽

New Evidence

IntroductionThe Victorian Department of Health and Human Services provided AUD 25 million (i.e. USD 17.3 million) over four years to determine the place of whole exome sequencing (WES) for patients attending public genetics clinics. Comparative analysis of WES and ‘usual care’ determined that WES increased diagnosis rate (from 14 to 58 percent), changed clinical management in one third of patients and identified relatives and couples at high risk of recurrence in future pregnancies. Translating this into routine care requires co-design with clinical and laboratory stakeholders.MethodsVictoria's clinical and laboratory genetics service system uses a ‘hub and spoke’ model. Representatives from these were invited to join a ‘Clinical Adoption Group’ (CAG) to oversight implementation of new government funding (AUD 2 million (i.e. USD 1.4 million) per year) to ensure statewide access to, and funding of, WES for children with rare undiagnosed genetic conditions. The CAG developed terms of reference, ‘traffic light’ evidence-based eligibility criteria, a pricing model and reporting mechanism, and recommended funding for sequencing, curation, curator training and multidisciplinary team (MDT) meetings to support implementation.ResultsFunding was distributed across hub and spoke sites reflecting clinical and laboratory demand and workforce requirements. All cases demonstrated clinical utility and were reviewed at MDT meetings. To date, 37 percent of patients have received a diagnosis changing management, with equity of access between metropolitan and regional areas demonstrated. Eligibility criteria are reviewed as new evidence is published to ensure new evidence is incorporated, although curation capacity limits turn-around-times.ConclusionsCo-designing a statewide and evidence-based clinical model has resulted in sector (i.e. clinician and laboratory) buy-in and supported broad access to funded WES. In addition, the sector has developed a better understanding of how evidence informs policy and funding decisions, which has resulted in delivering equitable WES that provides early diagnosis leading to changed clinical management and cessation of unnecessary interventions.

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