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Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases

Rare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for ra...

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Autores principales: Liu, Hong-Yan, Zhou, Liyuan, Zheng, Meng-Yue, Huang, Jia, Wan, Shu, Zhu, Aiying, Zhang, Mingjie, Dong, Anliang, Hou, Ling, Li, Jia, Xu, Haiming, Lu, Bingjian, Lu, Weiguo, Liu, Pengyuan, Lu, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920370/
https://www.ncbi.nlm.nih.gov/pubmed/31852928
http://dx.doi.org/10.1038/s41598-019-55832-1
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author Liu, Hong-Yan
Zhou, Liyuan
Zheng, Meng-Yue
Huang, Jia
Wan, Shu
Zhu, Aiying
Zhang, Mingjie
Dong, Anliang
Hou, Ling
Li, Jia
Xu, Haiming
Lu, Bingjian
Lu, Weiguo
Liu, Pengyuan
Lu, Yan
author_facet Liu, Hong-Yan
Zhou, Liyuan
Zheng, Meng-Yue
Huang, Jia
Wan, Shu
Zhu, Aiying
Zhang, Mingjie
Dong, Anliang
Hou, Ling
Li, Jia
Xu, Haiming
Lu, Bingjian
Lu, Weiguo
Liu, Pengyuan
Lu, Yan
author_sort Liu, Hong-Yan
collection PubMed
description Rare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for rare-disease management. In this study, 79 individuals from 16 independent families were performed for whole-genome sequencing (WGS) in an effort to identify the causative mutations for 16 distinct rare diseases that are largely clinically intractable. Comprehensive analysis of variations, including simple nucleotide variants (SNVs), copy-number variations (CNVs), and structural variations (SVs), was implemented using the WGS data. A flexible analysis pipeline that allowed a certain degree of misclassification of disease status was developed to facilitate the identification of causative variants. As a result, disease-causing variants were identified in 10 of the 16 investigated diseases, yielding a diagnostic rate of 62.5%. Additionally, new potentially pathogenic variants were discovered for two disorders, including IGF2/INS-IGF2 in mitochondrial disease and FBN3 in Klippel–Trenaunay–Weber syndrome. Our WGS analysis not only detected a CNV associated with 3p deletion syndrome but also captured a simple sequence repeat (SSR) variation associated with Machado–Joseph disease. To our knowledge, this is the first time the clinical WGS analysis of short-read sequences has been used successfully to identify a causative SSR variation that perfectly segregates with a repeat expansion disorder. After the WGS analysis, we confirmed the initial diagnosis for three of 10 established disorders and modified or corrected the initial diagnosis for the remaining seven disorders. In summary, clinical WGS is a powerful tool for the diagnosis of rare diseases, and its diagnostic clarity at molecular levels offers important benefits for the participating families.
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spelling pubmed-69203702019-12-20 Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases Liu, Hong-Yan Zhou, Liyuan Zheng, Meng-Yue Huang, Jia Wan, Shu Zhu, Aiying Zhang, Mingjie Dong, Anliang Hou, Ling Li, Jia Xu, Haiming Lu, Bingjian Lu, Weiguo Liu, Pengyuan Lu, Yan Sci Rep Article Rare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for rare-disease management. In this study, 79 individuals from 16 independent families were performed for whole-genome sequencing (WGS) in an effort to identify the causative mutations for 16 distinct rare diseases that are largely clinically intractable. Comprehensive analysis of variations, including simple nucleotide variants (SNVs), copy-number variations (CNVs), and structural variations (SVs), was implemented using the WGS data. A flexible analysis pipeline that allowed a certain degree of misclassification of disease status was developed to facilitate the identification of causative variants. As a result, disease-causing variants were identified in 10 of the 16 investigated diseases, yielding a diagnostic rate of 62.5%. Additionally, new potentially pathogenic variants were discovered for two disorders, including IGF2/INS-IGF2 in mitochondrial disease and FBN3 in Klippel–Trenaunay–Weber syndrome. Our WGS analysis not only detected a CNV associated with 3p deletion syndrome but also captured a simple sequence repeat (SSR) variation associated with Machado–Joseph disease. To our knowledge, this is the first time the clinical WGS analysis of short-read sequences has been used successfully to identify a causative SSR variation that perfectly segregates with a repeat expansion disorder. After the WGS analysis, we confirmed the initial diagnosis for three of 10 established disorders and modified or corrected the initial diagnosis for the remaining seven disorders. In summary, clinical WGS is a powerful tool for the diagnosis of rare diseases, and its diagnostic clarity at molecular levels offers important benefits for the participating families. Nature Publishing Group UK 2019-12-18 /pmc/articles/PMC6920370/ /pubmed/31852928 http://dx.doi.org/10.1038/s41598-019-55832-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Hong-Yan
Zhou, Liyuan
Zheng, Meng-Yue
Huang, Jia
Wan, Shu
Zhu, Aiying
Zhang, Mingjie
Dong, Anliang
Hou, Ling
Li, Jia
Xu, Haiming
Lu, Bingjian
Lu, Weiguo
Liu, Pengyuan
Lu, Yan
Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title_full Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title_fullStr Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title_full_unstemmed Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title_short Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases
title_sort diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed chinese families with rare diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920370/
https://www.ncbi.nlm.nih.gov/pubmed/31852928
http://dx.doi.org/10.1038/s41598-019-55832-1
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