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A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative

PURPOSE: Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. METHODS: In 38 ES negative patie...

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Autores principales: Shashi, Vandana, Schoch, Kelly, Spillmann, Rebecca, Cope, Heidi, Tan, Queenie K.-G., Walley, Nicole, Pena, Loren, McConkie-Rosell, Allyn, Jiang, Yong-Hui, Stong, Nicholas, Need, Anna C., Goldstein, David B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295275/
https://www.ncbi.nlm.nih.gov/pubmed/29907797
http://dx.doi.org/10.1038/s41436-018-0044-2
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author Shashi, Vandana
Schoch, Kelly
Spillmann, Rebecca
Cope, Heidi
Tan, Queenie K.-G.
Walley, Nicole
Pena, Loren
McConkie-Rosell, Allyn
Jiang, Yong-Hui
Stong, Nicholas
Need, Anna C.
Goldstein, David B.
author_facet Shashi, Vandana
Schoch, Kelly
Spillmann, Rebecca
Cope, Heidi
Tan, Queenie K.-G.
Walley, Nicole
Pena, Loren
McConkie-Rosell, Allyn
Jiang, Yong-Hui
Stong, Nicholas
Need, Anna C.
Goldstein, David B.
author_sort Shashi, Vandana
collection PubMed
description PURPOSE: Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. METHODS: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. RESULTS: Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). CONCLUSIONS: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.
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spelling pubmed-62952752018-12-15 A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative Shashi, Vandana Schoch, Kelly Spillmann, Rebecca Cope, Heidi Tan, Queenie K.-G. Walley, Nicole Pena, Loren McConkie-Rosell, Allyn Jiang, Yong-Hui Stong, Nicholas Need, Anna C. Goldstein, David B. Genet Med Article PURPOSE: Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. METHODS: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. RESULTS: Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). CONCLUSIONS: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives. 2018-06-15 2019-01 /pmc/articles/PMC6295275/ /pubmed/29907797 http://dx.doi.org/10.1038/s41436-018-0044-2 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Shashi, Vandana
Schoch, Kelly
Spillmann, Rebecca
Cope, Heidi
Tan, Queenie K.-G.
Walley, Nicole
Pena, Loren
McConkie-Rosell, Allyn
Jiang, Yong-Hui
Stong, Nicholas
Need, Anna C.
Goldstein, David B.
A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title_full A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title_fullStr A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title_full_unstemmed A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title_short A Comprehensive Iterative Approach is Highly Effective in Diagnosing Individuals who are Exome Negative
title_sort comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295275/
https://www.ncbi.nlm.nih.gov/pubmed/29907797
http://dx.doi.org/10.1038/s41436-018-0044-2
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