Association analysis between chromosomal abnormalities and fetal ultrasonographic soft markers based on 15,263 fetuses

Lijuan Pan; Jiayu Wu; Desheng Liang; Jing Yuan; Jue Wang; Yinchen Shen; Junjie Lu; Aihua Xia; Jinchen Li; Lingqian Wu

doi:10.1016/j.ajogmf.2023.101072

Association analysis between chromosomal abnormalities and fetal ultrasonographic soft markers based on 15,263 fetuses

Am J Obstet Gynecol MFM. 2023 Oct;5(10):101072. doi: 10.1016/j.ajogmf.2023.101072. Epub 2023 Jun 30.

Authors

Lijuan Pan¹, Jiayu Wu², Desheng Liang², Jing Yuan³, Jue Wang⁴, Yinchen Shen⁵, Junjie Lu⁶, Aihua Xia⁷, Jinchen Li⁸, Lingqian Wu⁹

Affiliations

¹ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Drs Pan, J Wu, Liang, and L Wu); Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan, China (Dr Pan).
² Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Drs Pan, J Wu, Liang, and L Wu).
³ Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (Dr Yuan).
⁴ Department of Obstetrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China (Dr Wang).
⁵ Department of Maternity Care, Nanning Maternity and Child Health Hospital, Nanning, Guangxi, China (Dr Shen).
⁶ Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Army Military Medical University, Chongqing, China (Dr Lu).
⁷ Department of Obstetrics, Beihai People's Hospital, Beihai, Guangxi, China (Dr Xia).
⁸ Bioinformatics Center and National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China (Dr Li). Electronic address: lijinchen@csu.edu.cn.
⁹ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Drs Pan, J Wu, Liang, and L Wu). Electronic address: wulingqian@sklmg.edu.cn.

PMID: 37393030
DOI: 10.1016/j.ajogmf.2023.101072

Abstract

Background: Soft markers are common prenatal ultrasonographic findings that indicate an increased risk for fetal aneuploidy. However, the association between soft markers and pathogenic or likely pathogenic copy number variations is still unclear, and clinicians lack clarity on which soft markers warrant a recommendation for invasive prenatal genetic testing of the fetus.

Objective: This study aimed to provide guidance on ordering prenatal genetic testing for fetuses with different soft markers and to elucidate the association between specific types of chromosomal abnormalities and specific ultrasonographic soft markers.

Study design: Low-pass genome sequencing was performed for 15,263 fetuses, including 9123 with ultrasonographic soft markers and 6140 with normal ultrasonographic findings. The detection rate of pathogenic or likely pathogenic copy number variants among fetuses with various ultrasonographic soft markers were compared with that of fetuses with normal ultrasonography. The association of soft markers with aneuploidy and pathogenic or likely pathogenic copy number variants were investigated using Fisher exact tests with Bonferroni correction.

Results: The detection rate of aneuploidy and pathogenic or likely pathogenic copy number variants was 3.04% (277/9123) and 3.40% (310/9123), respectively, in fetuses with ultrasonographic soft markers. An absent or a hypoplastic nasal bone was the soft marker in the second trimester with the highest diagnostic rate for aneuploidy of 5.22% (83/1591) among all isolated groups. Four types of isolated ultrasonographic soft markers, namely a thickened nuchal fold, single umbilical artery, mild ventriculomegaly, and absent or hypoplastic nasal bone, had higher diagnostic rates for pathogenic or likely pathogenic copy number variants (P<.05; odds ratio, 1.69-3.31). Furthermore, this study found that the 22q11.2 deletion was associated with an aberrant right subclavian artery, whereas the 16p13.11 deletion, 10q26.13-q26.3 deletion, and 8p23.3-p23.1 deletion were associated with a thickened nuchal fold, and the 16p11.2 deletion and 17p11.2 deletion were associated with mild ventriculomegaly (P<.05).

Conclusion: Ultrasonographic phenotype-based genetic testing should be considered in clinical consultations. Copy number variant analysis is recommended for fetuses with an isolated thickened nuchal fold, a single umbilical artery, mild ventriculomegaly, and an absent or a hypoplastic nasal bone. A comprehensive definition of genotype-phenotype correlations in aneuploidy and pathogenic or likely pathogenic copy number variants could provide better information for genetic counseling.

Keywords: aneuploidy; low-pass genome sequencing; pathogenic/likely pathogenic copy number variations; prenatal diagnosis; soft marker.