Diagnostic Yield of Sequencing in Prenatal Agenesis of the Corpus Callosum in a Well-Phenotyped International Cohort.

OBJECTIVE

To evaluate the incremental diagnostic yield of sequencing in a large, well-phenotyped international cohort of fetuses with prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify associated genes and variants.

METHODS

Retrospective multicenter cohort study of fetuses with a prenatal diagnosis of ACC undergoing sequencing after nondiagnostic chromosomal microarray. Clinical data were obtained from prenatal ultrasound and fetal MRI reports. Cases were classified as isolated ACC, ACC with additional central nervous system (CNS) abnormalities, or ACC with extracranial abnormalities. Variants were classified according to the ACMG or ACGS criteria.

RESULTS

Among 321 fetuses with ACC, a pathogenic or likely pathogenic (P/LP) variant was identified in 97 cases (30.2%). Diagnostic yield increased with phenotypic complexity: 17.3% in isolated ACC, 25.7% in ACC with additional CNS abnormalities, and 41.0% in ACC with extracranial abnormalities. MRI confirmation was available in 249 cases (77.6%) and did not alter overall diagnostic yield of genetic testing. No significant difference in yield was observed between complete ACC and other ACC types. P/LP variants were identified in 51 genes, most frequently TUBA1A.

CONCLUSION

Sequencing provides substantial diagnostic yield in prenatally diagnosed ACC, particularly when additional CNS or extracranial anomalies are present. These findings support the use of exome or genome sequencing in the prenatal evaluation of ACC and emphasize the importance of detailed phenotyping to improve classification, interpretation and counseling.