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Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis

Objective: Absence of homozygosity (AOH) is a genetic characteristic known to cause human diseases mainly through autosomal recessive or imprinting mechanisms. The importance and necessity of accurate AOH detection has become more clinically significant in recent years. However, it remains a challen...

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Autores principales: Lü, Yan, Jiang, Yulin, Zhou, Xiya, Hao, Na, Lü, Guizhen, Guo, Xiangxue, Guo, Ruidong, Liu, Wenjie, Xu, Chenlu, Chang, Jiazhen, Li, Mengmeng, Zhang, Hanzhe, Zhou, Jing, Zhang, Wei (Victor), Qi, Qingwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9914714/
https://www.ncbi.nlm.nih.gov/pubmed/36766665
http://dx.doi.org/10.3390/diagnostics13030560
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author Lü, Yan
Jiang, Yulin
Zhou, Xiya
Hao, Na
Lü, Guizhen
Guo, Xiangxue
Guo, Ruidong
Liu, Wenjie
Xu, Chenlu
Chang, Jiazhen
Li, Mengmeng
Zhang, Hanzhe
Zhou, Jing
Zhang, Wei (Victor)
Qi, Qingwei
author_facet Lü, Yan
Jiang, Yulin
Zhou, Xiya
Hao, Na
Lü, Guizhen
Guo, Xiangxue
Guo, Ruidong
Liu, Wenjie
Xu, Chenlu
Chang, Jiazhen
Li, Mengmeng
Zhang, Hanzhe
Zhou, Jing
Zhang, Wei (Victor)
Qi, Qingwei
author_sort Lü, Yan
collection PubMed
description Objective: Absence of homozygosity (AOH) is a genetic characteristic known to cause human diseases mainly through autosomal recessive or imprinting mechanisms. The importance and necessity of accurate AOH detection has become more clinically significant in recent years. However, it remains a challenging task for sequencing-based methods thus far. Methods: In this study, we developed and optimized a new bioinformatic algorithm based on the assessment of minimum sequencing coverage, optimal bin size, the Z-score threshold of four types of allele count and the frequency for accurate genotyping using 28 AOH negative samples, and redefined the AOH detection cutoff value. We showed the performance of chromosome analysis by five-fold coverage whole genome sequencing (CMA-seq) for AOH identification in 27 typical prenatal/postnatal AOH positive samples, which were previously confirmed by chromosomal microarray analysis with single nucleotide polymorphism array (CMA/SNP array). Results: The blinded study indicated that for all three forms of AOH, including whole genomic AOH, single chromosomal AOH and segmental AOH, and all kinds of sample types, including chorionic villus sampling, amniotic fluid, cord blood, peripheral blood and abortive tissue, CMA-seq showed equivalent detection power to that of routine CMA/SNP arrays (750K). The subtle difference between the two methods is that CMA-seq is prone to detect small inconsecutive AOHs, while CMA/SNP array reports it as a whole. Conclusion: Based on our newly developed bioinformatic algorithm, it is feasible to detect clinically significant AOH using CMA-seq in prenatal diagnosis.
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spelling pubmed-99147142023-02-11 Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis Lü, Yan Jiang, Yulin Zhou, Xiya Hao, Na Lü, Guizhen Guo, Xiangxue Guo, Ruidong Liu, Wenjie Xu, Chenlu Chang, Jiazhen Li, Mengmeng Zhang, Hanzhe Zhou, Jing Zhang, Wei (Victor) Qi, Qingwei Diagnostics (Basel) Article Objective: Absence of homozygosity (AOH) is a genetic characteristic known to cause human diseases mainly through autosomal recessive or imprinting mechanisms. The importance and necessity of accurate AOH detection has become more clinically significant in recent years. However, it remains a challenging task for sequencing-based methods thus far. Methods: In this study, we developed and optimized a new bioinformatic algorithm based on the assessment of minimum sequencing coverage, optimal bin size, the Z-score threshold of four types of allele count and the frequency for accurate genotyping using 28 AOH negative samples, and redefined the AOH detection cutoff value. We showed the performance of chromosome analysis by five-fold coverage whole genome sequencing (CMA-seq) for AOH identification in 27 typical prenatal/postnatal AOH positive samples, which were previously confirmed by chromosomal microarray analysis with single nucleotide polymorphism array (CMA/SNP array). Results: The blinded study indicated that for all three forms of AOH, including whole genomic AOH, single chromosomal AOH and segmental AOH, and all kinds of sample types, including chorionic villus sampling, amniotic fluid, cord blood, peripheral blood and abortive tissue, CMA-seq showed equivalent detection power to that of routine CMA/SNP arrays (750K). The subtle difference between the two methods is that CMA-seq is prone to detect small inconsecutive AOHs, while CMA/SNP array reports it as a whole. Conclusion: Based on our newly developed bioinformatic algorithm, it is feasible to detect clinically significant AOH using CMA-seq in prenatal diagnosis. MDPI 2023-02-02 /pmc/articles/PMC9914714/ /pubmed/36766665 http://dx.doi.org/10.3390/diagnostics13030560 Text en © 2023 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
Lü, Yan
Jiang, Yulin
Zhou, Xiya
Hao, Na
Lü, Guizhen
Guo, Xiangxue
Guo, Ruidong
Liu, Wenjie
Xu, Chenlu
Chang, Jiazhen
Li, Mengmeng
Zhang, Hanzhe
Zhou, Jing
Zhang, Wei (Victor)
Qi, Qingwei
Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title_full Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title_fullStr Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title_full_unstemmed Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title_short Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis
title_sort evaluation and analysis of absence of homozygosity (aoh) using chromosome analysis by medium coverage whole genome sequencing (cma-seq) in prenatal diagnosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9914714/
https://www.ncbi.nlm.nih.gov/pubmed/36766665
http://dx.doi.org/10.3390/diagnostics13030560
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