Abstract
Long continuous stretches of homozygosity (LCSH) are associated with risk of recessive disorders. Though LCSH can be detected by SNP microarrays, additional testing is necessary to clarify the clinical significance. This study is to assess the yield of additional exome sequencing (ES) after LCSH detection and inform the likelihood of eventual diagnosis. In 2226 patients referred to SNP microarrays, 35 patients met the criteria of indicative LCSH. These patients were recruited and went through additional ES. The diagnostic yield was analyzed, and the LCSH pattern was compared between eventually diagnosed cases and those undiagnosed. The results showed additional ES attained a diagnostic yield of 31.4% (11/35), but only one-third of the yield (11.4%, 4/35) was relevant to LCSH. In contrast, two-thirds of the diagnostic variants (20%, 7/35) were de novo or dominantly inherited, irrelevant to the original LCSH finding. No particular LCSH pattern, including the chromosomal coverage or LCSH size, was found to associate with the diagnostic outcome. We concluded that additional ES after LCSH detection could reveal diagnostic variants, but it is strongly recommended to consider all possible inheritance mode, as the diagnostic variants may be irrelevant to the original LCSH finding.
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Acknowledgements
We would like to acknowledge the affected individuals and their families for the participation in the study. This work was supported by the National Key R&D Program of China (No. 2019YFC1005100 and No. 2018YFC1002204, to YY); the National Natural Science Foundation of China (No. 81873735 and No. 81500972 to YF; No. 81670812 and No. 81873671, to YY); Shanghai Rising-Star Program (20QA1408200, to YF); the Jiaotong University Cross Biomedical Engineering (No. YG2017MS72, to YY); the Shanghai Municipal Commission of Health and Family Planning (No. 201740192, to YY); the Shanghai Shen Kang Hospital Development Center new frontier technology joint project (No. SHDC12017109, to YY); the Shanghai Science and Technology Commission (No. 19140904500, to YY); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20191908, to YY); Precision Medical Research of National Key Research and Development Program (2016YFC0905100, to WQ and XG).
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Fan, Y., Wang, L., Sun, Y. et al. Diagnostic yield of additional exome sequencing after the detection of long continuous stretches of homozygosity (LCSH) in SNP arrays. J Hum Genet 66, 409–417 (2021). https://doi.org/10.1038/s10038-020-00854-1
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DOI: https://doi.org/10.1038/s10038-020-00854-1
