Systematic Reanalysis of Genomic Data Improves Quality of Variant Interpretation

Overview

Journal Clin Genet

Specialty Genetics

Date 2018 Apr 14

PMID 29652076

Citations 21

Authors

S M Hiatt

M D Amaral

K M Bowling

C R Finnila

M L Thompson

D E Gray

J M J Lawlor

J N Cochran

E M Bebin

K B Brothers

K M East

W V Kelley

N E Lamb

S E Levy

E J Lose

M B Neu

C A Rich

S Simmons

R M Myers

G S Barsh

G M Cooper

Affiliations

Soon will be listed here.

Abstract

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Citing Articles

Tracking updates in clinical databases increases efficiency for variant reanalysis.

Li L, Tian X, Woodzell V, Gibbs R, Yuan B, Venner E Genet Med Open. 2024; 2:101841.

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Evolution of virtual gene panels over time and implications for genomic data re-analysis.

Robertson A, Tran K, Patel C, Sullivan C, Stark Z, Waddell N Genet Med Open. 2024; 1(1):100820.

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Exome sequencing data reanalysis of 200 hypertrophic cardiomyopathy patients: the HYPERGEN French cohort 5 years after the initial analysis.

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PMID: 39554508 PMC: 11565434. DOI: 10.3389/fmed.2024.1480947.

Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders.

Hiatt S, Lawlor J, Handley L, Latner D, Bonnstetter Z, Finnila C Genome Res. 2024; 34(11):1747-1762.

PMID: 39299904 PMC: 11610584. DOI: 10.1101/gr.279227.124.

Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders.

Hiatt S, Lawlor J, Handley L, Latner D, Bonnstetter Z, Finnila C medRxiv. 2024; .

PMID: 38585854 PMC: 10996728. DOI: 10.1101/2024.03.22.24304633.

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