Low-pass genome sequencing-based detection of absence of heterozygosity: validation in clinical cytogenetics

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Zirui Dong
  • Matthew Hoi Kin Chau
  • Yanyan Zhang
  • Zhenjun Yang
  • Mengmeng Shi
  • Yi Man Wah
  • Yvonne K. Kwok
  • Tak Yeung Leung
  • Kwong Wai Choy


Purpose: Absence of heterozygosity (AOH) is a genetic characteristic known to cause human genetic disorders through autosomal recessive or imprinting mechanisms. However, the analysis of AOH via low-pass genome sequencing (GS) is yet to be clinically available.
Methods: Low-pass GS (4-fold) with different types of libraries was performed on 17 clinical samples with previously ascertained AOH by chromosomal microarray analysis (CMA). In addition, AOH detection was performed with low-pass GS data in 1,639 cases that had both GS and high-probe-density CMA data available from the 1000 Genomes Project. Cases with multiple AOHs (coefficient of inbreeding F ≥1/32) or terminal AOHs ≥5-Mb (suspected uniparental disomy) were reported based on guidelines of the American College of Medical Genetics and Genomics.
Results: Low-pass GS revealed suspected segmental UPD and multiple AOHs (F≥1/32) in nine and eight clinical cases, respectively, consistent with CMA. Among the 1,639 samples, low-pass GS not only consistently detected multiple AOHs (F≥1/32) in 18 cases, but also reported 60 terminal AOHs in 44 cases including four mosaic AOHs at a level ranging from 50% to 75%.
Conclusion: Overall, our study demonstrates the feasibility of AOH analysis (≥5-Mb) with low-pass GS data and shows high concordance compared with CMA.

Bibliographical metadata

Original languageEnglish
JournalGenetics in Medicine
Publication statusAccepted/In press - 1 Feb 2021

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