Incremental yield of prenatal exome sequencing in fetuses with skeletal system abnormalities: A systematic review and...

Fetal skeletal abnormalities can be caused by various factors and genetic cause plays an important role. Prenatal exome sequencing (ES) has been shown to be a powerful approach for accurate prenatal molecular diagnoses. Diagnostic yield of ES in fetal skeletal abnormalities varies significantly across studies. This study aimed to perform a systematic review of the literature and meta-analysis to assess the incremental yield of ES in fetuses with different kinds of skeletal abnormalities and a negative result on chromosome microarray or karyotyping.

The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched up to November 26, 2022. Relevant data were collected from observational studies containing five or more cases of skeletal abnormalities who underwent ES. The incremental yield of ES was evaluated by single proportion analysis and 95% confidence interval (CI), both according to the article features and individual phenotypes. This study was registered on PROSPERO as CRD42022382800.

Twenty-six studies including 524 individuals met the inclusion criteria. The pooled incremental yield was 60.2% (95% CI, 53.4%-66.9%) for all fetuses with skeletal abnormalities. In subgroup analysis, the additional diagnostic yield was 83.9% (95% CI, 76.4%-90.4%) in isolated dysplasia cases (group I), 52.0% (95% CI, 32.9%-70.9%) in dysplasia with non-skeletal abnormalities cases (group II), 33.3% (95% CI, 19.3%-48.6%) in isolate dysostoses cases (group III), 47.8% (95 % CI, 35.8%-60.0%) in dysostoses with non-skeletal abnormalities cases (group IV), 83.0% (95% CI, 63.7%-97.1%) in combination of the two phenotypes without non-skeletal abnormalities cases (group V), 74.5% (95% CI, 54.9%-90.9%) in combination of the two phenotypes with non-skeletal abnormalities cases (group VI). The origin of the pathogenic variations differed among the groups. Most causative variants were de novo in groups I (97/133, 72.9%), V (14/23, 60.9%), and VI (15/26, 57.7%). Meanwhile, pathogenic variations in III (18/25, 72.0%) and IV (37/67, 55.2%) were more often inherited from a parent.

ES had a favorable incremental yield in fetuses with skeletal abnormalities. The common pathogenic variations and genetic patterns of skeletal abnormalities vary among different subtypes. Interpreting this difference is beneficial for personalized clinical consultation.