Prenatal Use of Exome Sequencing and Chromosomal Microarray Analysis: Indications, Interpretation, and Gene Selection Strategies

TL;DR

This review compares prenatal genetic tests CMA and exome sequencing, discussing their uses, interpretation challenges, and strategies for gene selection.

Contribution

The paper provides a comprehensive review of clinical indications and interpretation challenges for prenatal genomic testing methods.

Findings

CMA is becoming the standard prenatal genetic test for evaluating fetal structural anomalies.

Exome sequencing shows higher diagnostic yield with agnostic gene selection compared to phenotype-driven approaches.

Interpretation challenges remain for variants of uncertain significance and incidental findings in prenatal testing.

Abstract

As genomic technologies continue to evolve, understanding the scope and limitations of available prenatal testing methods is essential for accurate diagnosis and counseling. Chromosomal microarray analysis (CMA) and exome sequencing (ES) have emerged as key complementary tools in this setting. This review aims to outline the technical principles underlying CMA and ES and to compare their diagnostic capabilities and limitations in the prenatal context. This narrative review includes a literature search, with additional relevant articles identified through manual screening of reference lists from key publications and review articles. Due to the narrative nature of this review, no formal inclusion or exclusion criteria or quantitative synthesis were applied. Special focus was placed on clinical indications, variant interpretation challenges—particularly uncertain and incidental findings—gene selection strategies, and implications for prenatal counseling. Indications for both tests have increased over time but differ substantially. CMA is becoming the standard prenatal genetic test, particularly in the evaluation of fetal structural anomalies, whereas ES remains restricted to selected fetal structural anomalies. Interpretation of molecular results remains a major challenge, especially for variants of uncertain significance and incidental findings with unclear or unexpected implications for pregnancy management. For ES, agnostic gene selection strategies showed superior diagnostic yield compared with phenotype-driven approaches, likely reflecting the limited characterization of prenatal phenotypes. Continuous refinement of clinical indications, bioinformatic pipelines, variant classification criteria, and gene curation strategies is critical to ensure that prenatal results are accurate and clinically meaningful. Together, ongoing improvements in technology, interpretation, and clinical integration have the potential to transform prenatal genomics into a more precise, informed, and ethically responsible field.

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