Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses

作者：Fang Fu, Ru Li, Qiuxia Yu, Dan Wang, Qiong Deng, Lushan Li, Tingying Lei, Guilan Chen, Zhiqiang Nie, Xin Yang, Jin Han, Min Pan, Zhen Li, Yongling Zhang, Xiangyi Jing, Fucheng Li, Fatao Li, Lina Zhang, Cuixing Yi, Yingsi Li, Yan Lü, Hang Zhou, Ken Cheng, Li J, Lina Xiang, Jing Zhang, Sha Tang, Ping Fang, Dong‐Zhi Li, Can Liao · 发表于：Genome Medicine · 年份：2022 · DOI：10.1186/s13073-022-01130-x · 被引用次数：70 · 研究领域：Prenatal Screening and Diagnostics、Genomics and Rare Diseases、Genomic variations and chromosomal abnormalities

BACKGROUND: Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework. METHODS: We performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective (n=565) and prospective (n=1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed. RESULTS: A genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospect...