Genetic Investigation in Fetal Growth Restriction: An Integrated Approach for Clinical Practice

International guidelines recommend genetic testing when fetal growth restriction (FGR) accompanies structural anomalies, but recommendations for apparently isolated FGR remain variable, particularly regarding gestational age thresholds and the role of exome sequencing (ES). Interpretation is difficult because studies define FGR inconsistently, applying differing severity thresholds and "isolated" criteria, producing wide variation in reported yields. Chromosomal microarray analysis (CMA) provides an incremental yield of approximately 3% over karyotyping in isolated FGR, with pathogenic or likely pathogenic findings of 0%-8.1% across defined isolated subgroups, compared with approximately 10% in FGR with structural anomalies. After non-diagnostic CMA, ES yields pathogenic diagnoses in approximately 7%-18% of selected isolated cases and in over 30% of cohorts with structural anomalies. Fetal phenotype is the strongest predictor of ES yield, particularly in cases with disproportionately short long bones; the absence of clinical, Doppler, or biochemical evidence of placental insufficiency may indicate a higher genetic likelihood. Current ES data remain limited by small samples and heterogeneous definitions. The sFlt-1/PlGF ratio may distinguish placental-mediated from genetically determined growth restriction and refine selection for genomic testing, although this remains hypothesis-generating. We propose a phenotype-driven framework, applicable to singleton pregnancies, integrating sonographic phenotype, placental assessment, and prior screening to guide genetic testing in FGR.