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.