The Prenatal Phenotype: Illustrating the Complexities of Genetic Testing and Interpretation With the Goal of Understanding the Fetal Presentation of Genetic Disease

Advanced prenatal imaging and chromosomal microarray have improved detection of fetal anomalies, yet many structurally abnormal fetuses remain without a unifying diagnosis. This manuscript describes representative prenatal cases evaluated with genome sequencing (GS) or exome sequencing (ES), demonstrating how genomic data refine etiologic understanding, reshape counseling, and reveal the complexities of variant interpretation within the prenatal context. Three illustrative fetal cases were selected based on characteristic imaging findings, including short long bones, echogenic kidneys, multisystem anomalies, and severe limb reduction defects. All underwent detailed ultrasound, standard genetic evaluation, and ultimately GS or ES. Variants were classified using ACMG/AMP criteria with prenatal-specific interpretive considerations. Diagnoses included a 17q12 deletion with concomitant ARID1B-related Coffin-Siris syndrome, a de novo FRYL variant in the setting of multisystem anomalies, and a de novo KMT2E truncating variant identified alongside placental pathology supportive of treated leptospirosis. Findings alter recurrence risks, reveal dual diagnoses, and highlight prognostic complexities. Prenatal sequencing clarifies fetal diagnoses, informs reproductive planning, and refines risk counseling, yet interpretation is constrained by limited prenatal phenotyping and reliance on postnatal genotype-phenotype literature. Integration of GS/ES with imaging and multidisciplinary counseling is essential as sequencing becomes routine in perinatal care.