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Volume 13
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10.3390/diagnostics13030560
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Article

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

by
Yan Lü
1,
Yulin Jiang
1,
Xiya Zhou
1,
Na Hao
1,
Guizhen Lü
2,
Xiangxue Guo
2,
Ruidong Guo
2,
Wenjie Liu
2,
Chenlu Xu
2,
Jiazhen Chang
1,
Mengmeng Li
1,
Hanzhe Zhang
1,
Jing Zhou
1,
Wei (Victor) Zhang
2 and
Qingwei Qi
1,*
1
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China
2
AmCare Genomics Lab, Guangzhou 510335, China
*
Author to whom correspondence should be addressed.
Diagnostics 2023, 13(3), 560; https://doi.org/10.3390/diagnostics13030560
Submission received: 14 December 2022 / Revised: 29 January 2023 / Accepted: 30 January 2023 / Published: 2 February 2023
(This article belongs to the Special Issue Prenatal Diagnosis: Current Trends and Future Directions)
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Abstract

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.
Keywords: absence of homozygosity (AOH); medium coverage genome sequencing; chromosomal microarray analysis (CMA); prenatal diagnosis absence of homozygosity (AOH); medium coverage genome sequencing; chromosomal microarray analysis (CMA); prenatal diagnosis

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MDPI and ACS Style

Lü, Y.; Jiang, Y.; Zhou, X.; Hao, N.; Lü, G.; Guo, X.; Guo, R.; Liu, W.; Xu, C.; Chang, J.; et al. Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics 2023, 13, 560. https://doi.org/10.3390/diagnostics13030560

AMA Style

Lü Y, Jiang Y, Zhou X, Hao N, Lü G, Guo X, Guo R, Liu W, Xu C, Chang J, et al. Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics. 2023; 13(3):560. https://doi.org/10.3390/diagnostics13030560

Chicago/Turabian Style

Lü, Yan, Yulin Jiang, Xiya Zhou, Na Hao, Guizhen Lü, Xiangxue Guo, Ruidong Guo, Wenjie Liu, Chenlu Xu, Jiazhen Chang, and et al. 2023. "Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis" Diagnostics 13, no. 3: 560. https://doi.org/10.3390/diagnostics13030560

APA Style

Lü, Y., Jiang, Y., Zhou, X., Hao, N., Lü, G., Guo, X., Guo, R., Liu, W., Xu, C., Chang, J., Li, M., Zhang, H., Zhou, J., Zhang, W., & Qi, Q. (2023). Evaluation and Analysis of Absence of Homozygosity (AOH) Using Chromosome Analysis by Medium Coverage Whole Genome Sequencing (CMA-seq) in Prenatal Diagnosis. Diagnostics, 13(3), 560. https://doi.org/10.3390/diagnostics13030560

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