Comparison of Medium‐Coverage Whole‐Genome Sequencing and Chromosomal Microarray in Prenatal Testing of Absence of Heterozygosity

作者：Mengdie Zhang, Juan Li, Chunying Ren, Yaming Liu, Wuke Bian, Han Xiao, Mengru Wang, Xiaotian Chen, Yukun Hu, M. I. Kan, Ling Liu · 发表于：Prenatal Diagnosis · 年份：2026 · DOI：10.1002/pd.70218 · 研究领域：Genomics and Rare Diseases、Prenatal Screening and Diagnostics、Genetic Syndromes and Imprinting

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.