Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis

Matthew Hoi Kin Chau; Jicheng Qian; Zihan Chen; Ying Li; Yu Zheng; Wing Ting Tse; Yvonne K Kwok; Tak Yeung Leung; Zirui Dong; Kwong Wai Choy

doi:10.3389/fgene.2021.742325

Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis

Front Genet. 2021 Sep 20:12:742325. doi: 10.3389/fgene.2021.742325. eCollection 2021.

Authors

Matthew Hoi Kin Chau^{1

2

3}, Jicheng Qian^{1

2}, Zihan Chen², Ying Li^{1

2

3}, Yu Zheng^{1

2}, Wing Ting Tse¹, Yvonne K Kwok^{1

2}, Tak Yeung Leung^{1

2

4}, Zirui Dong^{1

2

3}, Kwong Wai Choy^{1

2

3

4}

Affiliations

¹ Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR China.
² Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Hong Kong, SAR China.
³ Hong Kong Hub of Pediatric Excellence, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR China.
⁴ The Chinese University of Hong Kong-Baylor College of Medicine Joint Center For Medical Genetics, Shatin, Hong Kong, SAR China.

Abstract

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management. Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies. Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5). Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.

Keywords: copy number variants; de novo; inherited; low-pass genome sequencing; prenatal diagnosis.