Clinical validity of phenotype-driven analysis software PhenoVar as a diagnostic aid for clinical geneticists in the interpretation of whole-exome sequencing data

Thuriot, Fanny; Buote, Caroline; Gravel, Elaine; Chénier, Sébastien; Désilets, Valerie; Maranda, Bruno; Waters, Paula J.; Jacques, Pierre-Étienne; Levesque, Sébastien

doi:10.1038/gim.2017.239

Cited by 15 publications

(20 citation statements)

References 32 publications

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“…1 Therefore, genetic testing is increasingly used and can be obtained in a noninvasive manner. Across different countries such as Canada, the United States, China, Korea, Germany, the United Kingdom, Egypt, Poland, Australia, and Japan, gene panel sequencing has a yield varying from 16% to 65%, [2][3][4][5][6][7] depending on subgroups of patients' selection, whereas exome sequencing has a yield in between 13% and 69% [8][9][10][11][12][13][14][15] in different settings. Its superiority over gene panel, in diagnosing common etiologies, remains to be quantified.…”

Section: Discussionmentioning

confidence: 99%

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Molecular diagnosis of muscular diseases in outpatient clinics

et al. 2020

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ObjectiveTo evaluate the diagnostic yield of an 89-gene panel in a large cohort of patients with suspected muscle disorders and to compare the diagnostic yield of gene panel and exome sequencing approaches.MethodsWe tested 1,236 patients from outpatient clinics across Canada using a gene panel and performed exome sequencing for 46 other patients with sequential analysis of 89 genes followed by all mendelian genes. Sequencing and analysis were performed in patients with muscle weakness or symptoms suggestive of a muscle disorder and showing at least 1 supporting clinical laboratory.ResultsWe identified a molecular diagnosis in 187 (15.1%) of the 1,236 patients tested with the 89-gene panel. Diagnoses were distributed across 40 different genes, but 6 (DMD, RYR1, CAPN3, PYGM, DYSF, and FKRP) explained about half of all cases. Cardiac anomalies, positive family history, age <60 years, and creatine kinase >1,000 IU/L were all associated with increased diagnostic yield. Exome sequencing identified a diagnosis in 10 (21.7%) of the 46 patients tested. Among these, 3 were attributed to genes not included in the 89-gene panel. Despite differences in median coverage, only 1 of the 187 diagnoses that were identified on gene panel in the 1,236 patients could have been potentially missed if exome sequencing had been performed instead.ConclusionsOur study supports the use of gene panel testing in patients with suspected muscle disorders from outpatient clinics. It also shows that exome sequencing has a low risk of missing diagnoses compared with gene panel, while potentially increasing the diagnostic yield of patients with muscle disorders.

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Section: Discussionmentioning

confidence: 99%

“…Exome sequencing was performed as previously described. 8 Briefly, it was performed at the McGill University and Génome Québec Innovation Centre (Montreal, Canada) or Glossary CK = creatine kinase; LGMD = limb-girdle muscular dystrophy; VUS = variants of uncertain significance. Fulgent (Temple City, CA).…”

Section: Exome Sequencingmentioning

confidence: 99%

Molecular diagnosis of muscular diseases in outpatient clinics

et al. 2020

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“…1, 2 The diagnostic rate of WES has been found to range from 30% to 40%, a variation that may be attributed to the numbers and phenotypes of enrolled patients and the various characteristics of study cohorts. [3][4][5][6][7][8][9][10] Whole genome studies such as WES are time-consuming and labor-intensive, requiring clinical geneticists and bioinformaticians to match large numbers of candidate variants with various clinical symptoms in each subject analyzed. 11 Moreover, in the absence of supporting data, many variants remain "variants of uncertain significance" (VUS), limiting the ability to confirm genetic diagnoses.…”

Section: Introductionmentioning

confidence: 99%

“…9,15,16 Although these approaches noticeably reduced the number of candidate variants responsible for the disease phenotype in each patient, these numbers varied among studies, without significantly improving genetic diagnosis rates, which have remained at about 30-35%. 5,16 This study describes a new, streamlined, automated interpretation system, termed EVIDENCE (3Billion, Inc., Seoul, South Korea), which interprets over 100,000 variants according to ACMG guidelines 17 and prioritizes variants based on each patient's phenotype within a few minutes. A symptom suggestion system based on Human Phenotype Ontology (HPO) was created to capture most patient phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…To date, more than 6300 genetic disorders and 4000 genes have been established on a molecular basis with the help of WES, and the numbers are still growing (1,2). Diagnostic yield was shown to vary according to the patient's phenotype, sample size, and cohort characteristics, while the average diagnostic rate of WES reported by various institutions is about 40% (3)(4)(5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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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

Seo

Kim

Park

et al. 2019

Preprint

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2 AbstractsPurpose: We developed an automated interpretation system for the whole process of Whole exome sequencing (WES) including raw data processing, variant calling, variant interpretation, and measurement of phenotypic similarity between the patient and each disease. This study was to investigate diagnostic yield and clinical utility of our new system that assists clinicians with diagnosis of patients with suspected genetic disorders. Methods: WES was performed a total of 194 patients (age range 0-68 years) with suspected genetic disorder. The patient inclusion criteria were delayed development within age of 5 months, multiple congenital anomalies with dysmorphic features, strongly suggestive features of monogenic disorder or genetically heterogeneous disorder, or not diagnosed despite performing genetic investigation. Results: WES reported 180 variants, of which 110 variants were confirmed by segregation analysis and 94 patients (48.4%) were diagnosed with 89 genetic disorders. There was no difference of diagnostic rate (48.9 %, 71/145 vs. 46.9%, 23/49, P > 0.05) and duration of the diagnostic odyssey (2.8 ± 3.3 vs. 4.1 ± 5.1, P= 0.293) between group with and without genetic test before WES. There was no significant difference in the distribution of clinical symptoms between the patients who were diagnosed with and without genetic disorder. Forty four percent of total patients filled only 9% of total symptom principal component analysis (PCA) space, and the remaining 56% of patients filled the other 91% of symptom PCA space. The two groups had similar genetic variant diversities (P = 0.899). ConclusionThis study showed improved diagnostic yield (48.4%) in patients with clinical heterogeneity by using automating variant interpretation. Diverse genetic variations were also observed in patients with similar symptoms. This study highlights the utility of automated 3 interpretation system of WES to clarify differential diagnosis in patients with suspected genetic disorder.

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Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency

Ritelli

Palagano

Cinquina

et al. 2020

Bone

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Clinical validity of phenotype-driven analysis software PhenoVar as a diagnostic aid for clinical geneticists in the interpretation of whole-exome sequencing data

Abstract: Phenotype-driven software prioritizes WES variants, provides an efficient diagnostic aid to clinical geneticists and laboratories, and should be incorporated in clinical practice.

Cited by 15 publications

References 32 publications

Molecular diagnosis of muscular diseases in outpatient clinics

Molecular diagnosis of muscular diseases in outpatient clinics

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

Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency

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