Whole-exome sequencing reveals genetic etiology and pregnancy outcomes in fetuses with ultrasound-detected abnormalities at a tertiary center.

Abstract

Despite advances in prenatal diagnostics, the genetic causes underlying fetal ultrasound abnormalities remain poorly understood, with a significant proportion of cases lacking definitive molecular diagnoses. Invasive prenatal testing was performed in 179 cases, followed by whole-exome sequencing (WES) to identify genetic etiologies. Among 179 abnormal fetuses, 132 had single-system and 47 had multisystem abnormalities. WES identified pathogenic (P) or likely pathogenic (LP) variants in 33 cases (19 single-system, 14 multisystem), with skeletal (7), cardiac (5), and craniofacial defects (2) being most frequent. Thirty-four genes were involved, encompassing 41 variants (15 missense, 10 frameshift, 6 splicing, 6 nonsense, and 4 in-frame deletions). WES yielded a P/LP rate of 17.88% (32/179) for variants that explained the fetal phenotype, with an additional pathogenic finding (overall P/LP rate: 18.44%, 33/179). Inheritance patterns were autosomal dominant (19), recessive (12), X-linked (1), and mosaic (1). Family studies confirmed 27 variants (18 inherited, 9 de novo). Pregnancy outcomes included 60 terminations, 19 intrauterine deaths, and 8 postnatal abnormalities. Most fetal ultrasound phenotypes matched the disease-causing gene profiles. Combining molecular testing with ultrasound helps clinicians identify genetic causes, assess recurrence risk, and inform parents, enabling personalized management for high-risk families.