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Clinical application of whole-exome sequencing: A retrospective, single-center study.

ABSTRACT: The aim of the present study was to assess the practical diagnostic value of whole-exome sequencing (WES) in patients with different phenotypes and to explore possible strategies to increase the capability of WES in identifying disease-causing genes. A total of 1,360 patients (aged from 1 day to 42 years old) with manifestations of genetic diseases were genotyped using WES and statistical analysis was performed on the results obtained. Within this cohort, the overall positive rate of identification of a disease-causing gene alteration was 44.41%. The positive identification rate where trio-samples were used (from the proband and both parents) was higher than that where a single proband sample was used (50.00 vs. 43.71%), and 604 positive cases with 150 genetic syndromes, 510 genes and 718 mutations were detected. Missense mutations were the most common variations (n=335, 45.27%) and visual or auditory abnormalities (58.51%) had the highest rate of association with a genetic abnormality. The positive detection rate of WES was elevated with the increase in the number of clinical symptoms from 1 to 8. The present study indicated that WES may be used as a valuable tool in the clinic and the positive rate depends more on the professional experience of clinicians rather than on the analytical capabilities of the data analyst. At the same time, particular attention must be paid to certain possible factors (such as the age of the patients as well as possible exon deletions), which may affect the diagnostic rate while applying this process.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC8135134 | biostudies-literature |

REPOSITORIES: biostudies-literature

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New insights from trio whole-exome sequencing in the children with kidney disease: A single-center retrospective cohort study.

Project description:BackgroundKidney disease of children markedly affects their health and development. Limited clinical data of early-stage kidney disease render a tremendous challenge for the accurate diagnosis. Trio whole-exome sequencing (Trio-WES) is emerging as a first-line diagnostic strategy in pediatric kidney disease, and shows important implications for the precision medicine strategies of children with kidney disease.MethodsTrio-WES was performed in 133 Chinese children with kidney disease and their parents. The results for casual variants in genes known to cause kidney disease were analyzed. We further assessed the genetic diagnostic yield and the clinical implications of genetic testing.ResultsAn overall diagnostic yield of 52.63% (70/133) was found, and the diagnostic rates ranged from 44.74% to 59.62% in different clinical phenotypes. The diagnostic yield of the three groups of simple proteinuria, renal insufficiency, and "other" was 50%, 50%, and 54.55%, respectively. Eight-seven diagnostic variants were identified in 70 probands with variants spanning 30 genes. The top 7 genes with diagnostic variants were COL4A5 (23, 26.44%), COL4A4 (13, 14.94%), ADCK4 (7, 8.05%), CLCN5 (3, 3.45%), ACE (3, 3.45%), PKD1 (3, 3.45%), and SLC12A3 (3, 3.45%), accounting for 63.22% of all variations in the cohort.ConclusionsThe retrospective cohort study summarized the clinical utility of genetic testing in 133 probands, and expanded the phenotypic and genetic profiles of kidney disease in children. Trio-WES is an efficient diagnostic tool for children with kidney disease, which facilitates the clinical diagnosis and treatment. Our findings have important implications for the precise diagnosis of childhood nephropathy and may provide clinical guideline for disease management.

| S-EPMC10337271 | biostudies-literature

Utility of Clinical Exome Sequencing in Dystonia: A Single-Center Study From India.

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| S-EPMC9171311 | biostudies-literature

A single-center pilot study in Malaysia on the clinical utility of whole-exome sequencing for inborn errors of immunity.

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| S-EPMC4211433 | biostudies-other

Clinical Application of Whole Exome Sequencing for Monogenic Disorders in PICU of China.

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

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders.

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| S-EPMC7699758 | biostudies-literature

Concordance between whole-exome sequencing and clinical Sanger sequencing: implications for patient care.

Project description:The clinical translation of next-generation sequencing has created a paradigm shift in the diagnostic assessment of individuals with suspected rare genetic diseases. Whole-exome sequencing (WES) simultaneously examines the majority of the coding portion of the genome and is rapidly becoming accepted as an efficient alternative to clinical Sanger sequencing for diagnosing genetically heterogeneous disorders. Among reports of the clinical and diagnostic utility of WES, few studies to date have directly compared its concordance to Sanger sequencing, which is considered the clinical "gold standard". We performed a direct comparison of 391 coding and noncoding polymorphisms and variants of unknown significance identified by clinical Sanger sequencing to the WES results of 26 patients. Of the 150 well-covered coding variants identified by Sanger sequencing, 146 (97.3%) were also reported by WES. Nine genes were excluded from the comparison due to consistently low coverage in WES, which might be attributed to the use of older exome capture kits. We performed confirmatory Sanger sequencing of discordant variants; including five variants with discordant bases and four with discordant zygosity. Confirmatory Sanger sequencing supported the original Sanger report for three of the five discordant bases, one was shown to be a false positive supporting the WES data, and one result differed from both the Sanger and WES data. Two of the discordant zygosity results supported Sanger and the other two supported WES data. We report high concordance for well-covered coding variants, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the use of supplementary Sanger sequencing for poorly-covered genes when the clinical suspicion is high. Importantly, despite remaining difficulties with achieving complete coverage of the whole exome, 10 (38.5%) of the 26 compared patients were diagnosed through WES.

| S-EPMC5023935 | biostudies-other

Whole-exome sequencing study of hypospadias.

Project description:Hypospadias results from the impaired urethral development, which is influenced by androgens, but its genetic etiology is still unknown. Through whole exome sequencing analysis, we identified NR5A1, SRD5A2, and AR as mutational hotspots in the etiology of severe hypospadias, as these genes are related to androgen signaling. Additionally, rare damaging variants in cilia-related outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 8.5 × 10-47) were significantly enriched in hypospadias cases. The Dnah8 KO mice exhibited significantly decreased testosterone levels, which had an impact on urethral development and disrupted steroid biosynthesis. Combined with trios data, transcriptomic, and phenotypical and proteomic characterization of a mouse model, our work links ciliary genes with hypospadias. Overall, a panel of ODNAH genes with rare damaging variants was identified in 24% of hypospadias patients, providing significant insights into the underlying pathogenesis of hypospadias as well as genetic counseling.

| S-EPMC10165268 | biostudies-literature

Application of Whole Exome Sequencing in Congenital Secretory Diarrhea Diagnosis.

Project description: Not available

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Clinical whole-exome sequencing results impact medical management.

Project description:BACKGROUND:Clinical diagnostic whole-exome sequencing (WES) is a powerful tool for patients with undiagnosed genetic disorders. To demonstrate the clinical utility, we surveyed healthcare providers (HCP) about changes in medical management and treatment, diagnostic testing, reproductive planning, and use of educational services subsequent to WES testing. METHODS:For a period of 18 months, an 18-question survey was sent to HCPs attached to the WES reports. We analyzed the molecular diagnosis, patient clinical features, and the medical management changes reported in the returned surveys. RESULTS:A total of 62 (2.2% of 2,876) surveys were returned, consisting of 37.1% patients with a positive or likely positive pathogenic alteration, 51.6% negative results, 9.7% uncertain findings, and 1 patient (1.6%) with a novel candidate finding. Overall, 100% of the HCPs of patients with positive or likely positive WES results (n = 23) and HCPs of patients with uncertain WES results (n = 6) responded positively to one of the 18 queries. Of note, 37.5% of the HCPs of patients with negative WES results (n = 32) responded positively to at least one query. CONCLUSION:Overall, these data clearly demonstrate the clinical utility of WES by demonstrating the impact on medical management irrespective of the exome result.

| S-EPMC6305629 | biostudies-literature

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