Comparison of Medium‐Coverage Whole‐Genome Sequencing and Chromosomal Microarray in Prenatal Testing of Absence of Heterozygosity
Mengdie Zhang, Juan Li, Chunying Ren, Yaming Liu, Wuke Bian, Xiao Han, Mengru Wang, Xiaotian Chen, Yukun Hu, Meilin Kan, Ling LiuABSTRACT
Objective
Absence of heterozygosity (AOH) is a clinically significant genomic feature often associated with uniparental disomy and parental consanguinity in the prenatal settings. Chromosomal microarray analysis (CMA) is commonly used for AOH detection, while sequencing‐based approaches may provide complementary genomic information within a single assay. This study evaluated the performance of medium‐coverage whole‐genome sequencing (CNV‐plus) for the detection of prenatal AOH.
Methods
We analyzed 45 prenatal samples (35‐CMA‐positive, 10‐CMA‐negative). Concordance between CNV‐plus and CMA was assessed at regional, genome‐wide, and sample levels, with particular emphasis on the effect of AOH segment size.
Results
CNV‐plus detected 56 AOH regions compared with 65 by CMA, yielding 68 matched segments. Segment‐level sensitivity was 86.8%, showing clear size dependence: 53.3% for 5–10 Mb regions and 96.2% for regions > 10 Mb. Genome‐wide overlap was high (global Jaccard index = 0.871), although boundary resolution differed between methods. At the sample level, CNV‐plus achieved 97.1% sensitivity and 100% specificity, with no significant difference from CMA.
Conclusions
CNV‐plus demonstrates good concordance with CMA for detecting larger AOH regions in prenatal samples and may serve as a complementary approach when considering its size‐dependent performance.