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A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome seque...

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Autores principales: Huang, Jie, Liu, Jun, Tian, Ruiyi, Liu, Kevin, Zhuang, Patrick, Sherman, Hannah Tayla, Budjan, Christoph, Fong, Michelle, Jeong, Min-Seo, Kong, Xue-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750892/
https://www.ncbi.nlm.nih.gov/pubmed/35011571
http://dx.doi.org/10.3390/cells11010010
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author Huang, Jie
Liu, Jun
Tian, Ruiyi
Liu, Kevin
Zhuang, Patrick
Sherman, Hannah Tayla
Budjan, Christoph
Fong, Michelle
Jeong, Min-Seo
Kong, Xue-Jun
author_facet Huang, Jie
Liu, Jun
Tian, Ruiyi
Liu, Kevin
Zhuang, Patrick
Sherman, Hannah Tayla
Budjan, Christoph
Fong, Michelle
Jeong, Min-Seo
Kong, Xue-Jun
author_sort Huang, Jie
collection PubMed
description Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We confirmed a portion of the key variants with Sanger sequencing and provided interpretation with consideration of patients’ clinical symptoms and detailed literature review. Furthermore, we showed that identification of the genetic contributions of ASD core symptoms and comorbidities may promote a better understanding of the ASD pathophysiology, lead to early detection of associated comorbidities, and facilitate pharmacologic intervention based on pathological pathways inferred from the genetic information. We will make the bioinformatics pipeline and interpretation framework publicly available, in an easily accessible format, after validation with a larger cohort. We hope that the present proposed protocol can serve as a starting point to invite discourse and debate to further improve approaches in WGS-based genetic consultation for patients with ASD.
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spelling pubmed-87508922022-01-12 A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder Huang, Jie Liu, Jun Tian, Ruiyi Liu, Kevin Zhuang, Patrick Sherman, Hannah Tayla Budjan, Christoph Fong, Michelle Jeong, Min-Seo Kong, Xue-Jun Cells Article Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We confirmed a portion of the key variants with Sanger sequencing and provided interpretation with consideration of patients’ clinical symptoms and detailed literature review. Furthermore, we showed that identification of the genetic contributions of ASD core symptoms and comorbidities may promote a better understanding of the ASD pathophysiology, lead to early detection of associated comorbidities, and facilitate pharmacologic intervention based on pathological pathways inferred from the genetic information. We will make the bioinformatics pipeline and interpretation framework publicly available, in an easily accessible format, after validation with a larger cohort. We hope that the present proposed protocol can serve as a starting point to invite discourse and debate to further improve approaches in WGS-based genetic consultation for patients with ASD. MDPI 2021-12-21 /pmc/articles/PMC8750892/ /pubmed/35011571 http://dx.doi.org/10.3390/cells11010010 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Jie
Liu, Jun
Tian, Ruiyi
Liu, Kevin
Zhuang, Patrick
Sherman, Hannah Tayla
Budjan, Christoph
Fong, Michelle
Jeong, Min-Seo
Kong, Xue-Jun
A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title_full A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title_fullStr A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title_full_unstemmed A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title_short A Next Generation Sequencing-Based Protocol for Screening of Variants of Concern in Autism Spectrum Disorder
title_sort next generation sequencing-based protocol for screening of variants of concern in autism spectrum disorder
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750892/
https://www.ncbi.nlm.nih.gov/pubmed/35011571
http://dx.doi.org/10.3390/cells11010010
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