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

• DOI: 10.1186/s13073-022-01130-x
• Publication Date: 2022-10-28T09:13:25Z
• Authors: Fang Fu; Ru Li; Qiuxia Yu; Dan Wang; Qiong Deng; Lushan Li; Tingying Lei; Guilan Chen; Zhiqiang Nie; Xin Yang; Jin Han; Min Pan; Li Zhen; Yongling Zhang; Xiangyi Jing; Fucheng Li; Fatao Li; Lina Zhang; Cuixing Yi; Yingsi Li; Yan Lu; Hang Zhou; Ken Cheng; Jian Li; Lina Xiang; Jing Zhang; Sha Tang; Ping Fang; Dongzhi Li; Can Liao
• Keywords: Exome

Abstract Background Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into management remain limited practice. Herein, we report our experience implementing ES (pES) a large cohort of fetuses with anomalies detected by ultrasonography using hospital-based in-house multidisciplinary team (MDT) facilitated three-step genotype-driven followed phenotype-driven analysis framework. Methods We performed pES 1618 fetal cases positive ultrasound findings but negative for karyotyping chromosome microarray between January 2014 October 2021, including both retrospective ( n =565) prospective =1053) cohorts. The diagnostic efficiency correlation to organ systems involved, phenotypic spectrum, the impacts results pregnancy outcomes were analyzed. Results A approach was carried out all trio pES. Step 1, resulted rate 11.6% (187/1618). 2, comprehensive yielded additional another 28 (1.7%; 28/1618). In final step 3, reanalyses based new phenotypes and/or requests found molecular diagnosis 14 (0.9%; 14/1618). Altogether, 229 (14.2%) received diagnosis, higher than (17.3% vs. 12.4%, p <0.01). rates highest skeletal (30.4%) multiple involvements (25.9%), lowest chest (0%). addition, incidental secondary childhood-onset disorders 11 (0.7%) cases. Furthermore, described first time 27 gene-associated conditions (20.0%, 27/135) upon systematic diagnosed expanded phenotype spectrum 26 (19.3%) genes where information available. cohort, combined had significantly impacted decisions (61.5%, 648/1053). Conclusions could identify about 81.7% (11.6% total cohort) initial considered. following two steps helped us find causative variants an 2.6% entire (18.3% findings). Our extensive number molecularly confirmed greatly enriched current knowledge phenotype-genotype correlation, which may guide focused future. This far largest study that combines robust sequence analysis, well-established MDT single setting. work underlines value as essential component guiding medical parental decision making.