Genetic diagnostic yield of prenatal testing for fetal central nervous system abnormalities: a phenotype-driven study in a large single-center cohort

This retrospective single-centre study includes 966 fetuses with central nervous system abnormalities detected by prenatal ultrasound and/or fetal MRI, all tested by CNV-seq, with karyotyping and trio exome sequencing performed according to clinical indication and parental preference. Pathogenic or likely pathogenic variants were identified in 12.63% of cases: CNV-seq yield was 8.07% (78/966), trio exome yield 16.32% (70/429), with an additional 10.92% (44/403) after negative CNV-seq. CNV-seq yield was higher in non-isolated cases (15.41% vs 4.25%), and exome yield higher in isolated-complex than isolated-single cases (32.56% vs 9.20%). After excluding mild isolated CNS anomalies, yields reached 15.60% for CNV-seq and 26.67% for exome, and yield increased with severity for ventriculomegaly and reduced head circumference.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Useful figures for prenatal counseling: trio exome sequencing yields a diagnosis in about one fetus in ten after negative CNV-seq, and in nearly one in three among isolated but complex central nervous system anomalies. Stratification by imaging phenotype helps prioritize indications, particularly for isolated mild findings, whose yield is lower. A retrospective single-centre study in which exome sequencing was performed in only part of the fetuses, according to indication and parental preference: selection bias weighs on exome yields.

Analysis by Dr Thibaut Benquey