Exome sequencing and prenatal skeletal abnormalities: comprehensive review and meta-analysis and way forward

Abstract

Objective: To assess the detection rate of exome sequencing (ES) in fetuses diagnosed as skeletal abnormalities (SKA) with normal karyotype or chromosomal microarray analysis (CMA) results.

Methods: We conducted electronic searches in four databases, focusing on studies involving ES in fetuses with SKA. Additional detection rate of ES compared to karyotype/CMA was calculated, followed by a meta-analysis. Subgroup analyses explored the influence of fetal phenotype on diagnostic outcomes.

Results: From 2,393 studies, 21 reports covering 476 fetuses were analyzed. Key findings include: (1) an additional detection rate of ES of 63.2% (Risk Difference (RD), 0.68 [95% CI, 0.60-0.76], p < 0.00001); (2) identification of 76 genes across 304 types of variants, with FGFR3, COL1A1, COL1A2, and COL2A1 being prevalent; (3) lower detection rates in fetuses with isolated short long bones compared to non-isolated conditions, though not significantly different (p = 0.35); (4) higher detection rates in subgroups with abnormal ossification, small chest, suspected long bone fractures or angulations, and skull abnormalities.

Conclusion: The meta-analysis indicates that genetic variation significantly contributes to fetal SKA, primarily due to single-gene variants. Consequently, ES should be used in the prenatal diagnosis of SKA fetuses in clinical practice.

Keywords: chromosomal microarray analysis; exome sequencing; karyotyping; prenatal diagnosis; skeletal abnormalities.

FIGURE 1

PRISMA flow diagram showing study screening and selection.