Targeted fetal NGS panel reveals genetic conditions in sonographically normal fetuses: Insights from a large cohort study

Abstract

Prenatal genetic testing plays a crucial role in prenatal diagnosis and is traditionally performed when abnormalities are detected on fetal ultrasound. With the widespread availability of next-generation sequencing (NGS), genetic screening is increasingly being applied to fetuses with normal ultrasound findings. This study aimed to evaluate the diagnostic yield and outcomes of NGS panel testing in a large cohort of pregnant women with sonographically normal fetuses. A retrospective analysis was conducted on 1,820 sonographically normal fetuses that underwent fetal NGS-targeted panel testing based on parental requests between June 2021 and June 2023. Among the 1,820 cases analyzed, no pathogenic mutations were identified in 833 (45.8%), 893 (49.1%) had an abnormal carrier status, and 94 (5.2%) exhibited pathogenic conditions, including 25 autosomal dominant, 29 autosomal recessive, 39 X-linked (35 hemizygous glucose-6-phosphate dehydrogenase [ G6PD ] cases), and one mitochondrial disorder. The most common autosomal recessive mutation was a homozygous pathogenic variant of GJB2 (19 cases). Furthermore, 48 patients carried heterozygous G6PD mutations, and 344 patients were identified as carriers of GJB2 variants. Other notable findings included 15 cases of familial hypercholesterolemia, five cases of Noonan syndrome, and two cases of osteogenesis imperfecta. The rare disorders identified were Wilson’s disease, cystic fibrosis, Cockayne syndrome, and ototoxic hearing loss, all of which were observed in a single case. A fetal NGS-targeted panel yielded critical findings in 5.16% of sonographically normal fetuses, emphasizing its potential use in prenatal diagnosis. Effective screening requires careful variant selection and detailed pre- and post-test genetic counseling to ensure the clinical relevance and informed decision-making of parents.