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Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

ABSTRACT: Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

SUBMITTER: Bertoli-Avella AM

PROVIDER: S-EPMC7852664 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella Aida M AM Beetz Christian C Ameziane Najim N Rocha Maria Eugenia ME Guatibonza Pilar P Pereira Catarina C Calvo Maria M Herrera-Ordonez Natalia N Segura-Castel Monica M Diego-Alvarez Dan D Zawada Michal M Kandaswamy Krishna K KK Werber Martin M Paknia Omid O Zielske Susan S Ugrinovski Dimitar D Warnack Gitte G Kampe Kapil K Iurașcu Marius-Ionuț MI Cozma Claudia C Vogel Florian F Alhashem Amal A Hertecant Jozef J Al-Shamsi Aisha M AM Alswaid Abdulrahman Faiz AF Eyaid Wafaa W Al Mutairi Fuad F Alfares Ahmed A Albalwi Mohammed A MA Alfadhel Majid M Al-Sannaa Nouriya Abbas NA Reardon Willie W Alanay Yasemin Y Rolfs Arndt A Bauer Peter P

European journal of human genetics : EJHG 20200828 1

Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknow ...[more]

PMID: 32860008

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Project description:BackgroundAs the novel serum biomarkers, it has not been clearly clarified that the diagnostic accuracy of prostate health index (PHI) and prostate health index density (PHID) are superior to that of percentage free prostate-specific antigen (%fPSA) in detection of clinically significant prostate cancer (csPCa), especially in the gray zone. Therefore, this study aimed to compare the diagnostic value of PHI, PHID, and %fPSA for csPCa in the patients with prostate-specific antigen (PSA) >4 ng/mL and those with PSA within 4-10 ng/mL.MethodsIn this study, the serum samples and clinicopathological features were prospectively obtained from the patients who underwent prostate biopsy between September 2019 and December 2020. According to the inclusion criteria, the patients with total PSA (tPSA) >4 ng/mL, prostate magnetic resonance imaging or ultrasound clearly suggesting an occupying lesion were enrolled in this study. The patients with Gleason score ≥7 indicated csPCa. The receiver operating characteristic curves and the area under the curve (AUC) values were used to assess the diagnostic performance.ResultsAmong the 296 patients (mean age 67.5 years, median tPSA 7.94 ng/mL) included in this study, there were 54 in the csPCa group (mean age 70.4 years, median tPSA 11.0 ng/mL) and 242 in the non-csPCa group (mean age 66.8 years, median tPSA 7.67 ng/mL). Based on the PSA level, there were 198 patients with PSA within the gray zone, which included 40 patients in the csPCa group and 158 in the non-csPCa group. In all patients, the sensitivity of PHID for detecting csPCa was 96.30%, and the specificity was 33.06% with the cut-off value of 0.51. Moreover, both PHID and PHI did better in the diagnosis of csPCa (AUC: 0.880 and 0.867, respectively) compared with other PSA derivative markers. Similarly, in the patients with PSA level in the gray zone, the diagnostic accuracy of PHID and PHI in predicting csPCa (AUC: 0.788 and 0.777, respectively) were better than other PSA derivative markers.ConclusionsPHID presented the better diagnostic accuracy in predicting csPCa in patients with PSA in the gray zone than other PSA derivative markers, which could be a promising biomarker for making the biopsy strategy.

Dataset Information

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Publications

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

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