From Isolated to Complex: Diagnostic Yield of Chromosomal Microarray and Exome Sequencing in Fetal Growth Restriction

OBJECTIVE: To characterize the overall diagnostic yield of sequential chromosomal microarray (CMA) and exome sequencing (ES) across the phenotypic spectrum of fetal growth restriction (FGR). METHODS: A retrospective cohort of 320 consecutive FGR pregnancies presenting at ≥ 20 weeks to a tertiary fetal medicine unit (2020-2025). All patients underwent a dedicated anatomical survey, including neurosonography. Cases were classified as isolated or non-isolated and characterized by organ system, severity, gestational age at onset, and Doppler status. Genetic counseling was offered to all patients. RESULTS: FGR was isolated in 199/320 (62.2%) and non-isolated in 121/320 (37.8%); 218/320 (68.1%) were early-onset (< 32 weeks) and 96/320 (30%) had abnormal Doppler. CMA was performed in 237/320 (74.1%), yielding an abnormality in 5.5% (13/237). Of these, only 5/237 (2.1%) were considered causative of the FGR phenotype. ES was performed in 149/320 (46.6%), with an overall FGR-causative yield of 10.7% (16/149), significantly higher in non-isolated versus isolated cases (18.5% vs. 4.8%; p = 0.014). Abnormal Doppler did not preclude a monogenic diagnosis (5/16 FGR-causative cases). CONCLUSIONS: FGR carries a substantial genetic yield, supporting stratified testing across the phenotypic spectrum. A monogenic diagnosis and placental vascular disease are not mutually exclusive. A molecular etiology provides information for counseling, recurrence-risk assessment, and reproductive planning, regardless of outcome.