Abstract
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.
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.
| Original language | English |
|---|---|
| Journal | Genetics in Medicine |
| Publication status | Accepted/In press - 1 Feb 2021 |
Fingerprint
Dive into the research topics of 'Low-pass genome sequencing-based detection of absence of heterozygosity: validation in clinical cytogenetics'. Together they form a unique fingerprint.Projects
-
Manchester Centre for Audiology and Deafness (ManCAD)
Munro, K. (PI), Millman, R. (PI), Lamb, W. (Support team), Dawes, P. (PI), Plack, C. (PI), Stone, M. (PI), Kluk-De Kort, K. (PI), Moore, D. (PI), Morton, C. (PI), Prendergast, G. (PI), Couth, S. (PI), Schlittenlacher, J. (PI), Chilton, H. (PI), Visram, A. (Researcher), Dillon, H. (PI), Guest, H. (Researcher), Heinrich, A. (PI), Jackson, I. (Researcher), Littlejohn, J. (Researcher), Jones, L. (PI), Lough, M. (Researcher), Morgan, R. (Researcher), Perugia, E. (Researcher), Roughley, A. (Researcher), Whiston, H. (Researcher), Wright, C. (Support team), Saunders, G. (PI), Kelly, C. (PI), Cross, H. (Researcher), Loughran, M. (Researcher), Hoseinabadi, R. (PI) & Vercammen, C. (PI)
Project: Research