Transcriptome analysis provides critical answers to the “variants of uncertain significance” conundrum

While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA‐level data fails to identify the underlying genetic etiology. Specifically, patients of non‐White race and n...

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Published inHuman mutation Vol. 43; no. 11; pp. 1590 - 1608
Main Authors Postel, Mackenzie D., Culver, Julie O., Ricker, Charité, Craig, David W.
Format Journal Article
LanguageEnglish
Published United States Hindawi Limited 01.11.2022
John Wiley and Sons Inc
Subjects
deep intronic variants
Etiology
Gene Expression Profiling
genetic ancestry
Genetic Predisposition to Disease
Genetic Testing
Genetic Variation
Genomes
Humans
Introns
Precision medicine
Reclassification
Review
Reviews
RNA
splicing variants
Transcriptomes
variants of uncertain significance
variants of unknown significance
splicing variants
genetic ancestry
variants of unknown significance
deep intronic variants
variants of uncertain significance
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Abstract While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA‐level data fails to identify the underlying genetic etiology. Specifically, patients of non‐White race and non‐European ancestry are disproportionately affected by “variants of unknown/uncertain significance” (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non‐neoplastic diseases. RNA data tips the scales of molecular evidence, clarifying variants as benign or pathogenic.
AbstractList While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA-level data fails to identify the underlying genetic etiology. Specifically, patients of non-White race and non-European ancestry are disproportionately affected by "variants of unknown/uncertain significance" (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non-neoplastic diseases.While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA-level data fails to identify the underlying genetic etiology. Specifically, patients of non-White race and non-European ancestry are disproportionately affected by "variants of unknown/uncertain significance" (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non-neoplastic diseases.
While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA‐level data fails to identify the underlying genetic etiology. Specifically, patients of non‐White race and non‐European ancestry are disproportionately affected by “variants of unknown/uncertain significance” (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non‐neoplastic diseases.
While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA‐level data fails to identify the underlying genetic etiology. Specifically, patients of non‐White race and non‐European ancestry are disproportionately affected by “variants of unknown/uncertain significance” (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non‐neoplastic diseases. RNA data tips the scales of molecular evidence, clarifying variants as benign or pathogenic.
Author Ricker, Charité
Culver, Julie O.
Postel, Mackenzie D.
Craig, David W.
AuthorAffiliation 1 Department of Translational Genomics University of Southern California Los Angeles California USA
2 Keck School of Medicine of USC University of Southern California Los Angeles California USA
AuthorAffiliation_xml – name: 1 Department of Translational Genomics University of Southern California Los Angeles California USA
– name: 2 Keck School of Medicine of USC University of Southern California Los Angeles California USA
Author_xml – sequence: 1
  givenname: Mackenzie D.
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  surname: Postel
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  surname: Culver
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  surname: Ricker
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  orcidid: 0000-0003-2040-1955
  surname: Craig
  fullname: Craig, David W.
  email: davidwcr@usc.edu
  organization: University of Southern California
BackLink https://www.ncbi.nlm.nih.gov/pubmed/35510381$$D View this record in MEDLINE/PubMed
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Issue 11
Keywords splicing variants
genetic ancestry
variants of unknown significance
deep intronic variants
variants of uncertain significance
Language English
License Attribution-NonCommercial
2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
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2021; 13
2021; 16
2018; 2018
2020; 2065
2021; 12
2021; 11
2022
2021
2020
2021; 18
2017; 10
2021; 17
2015; 21
2019
2018
2017
2021; 175
2017; 19
2016
2015
2012; 6
2018; 59
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Snippet While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions...
While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions...
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SubjectTerms deep intronic variants
Etiology
Gene Expression Profiling
genetic ancestry
Genetic Predisposition to Disease
Genetic Testing
Genetic Variation
Genomes
Humans
Introns
Precision medicine
Reclassification
Review
Reviews
RNA
splicing variants
Transcriptomes
variants of uncertain significance
variants of unknown significance
Title Transcriptome analysis provides critical answers to the “variants of uncertain significance” conundrum
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fhumu.24394
https://www.ncbi.nlm.nih.gov/pubmed/35510381
https://www.proquest.com/docview/2723509439/abstract/
https://www.proquest.com/docview/2660102632/abstract/
https://pubmed.ncbi.nlm.nih.gov/PMC9560997
Volume 43
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