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

Sequencing after a non-diagnostic chromosomal microarray in fetuses with agenesis of the corpus callosum, with yield increasing with phenotypic complexity and 51 genes identified, TUBA1A being the most frequent

The authors evaluated the incremental diagnostic yield of sequencing in a large, well-phenotyped international cohort of fetuses with prenatally diagnosed agenesis of the corpus callosum (ACC), in order to identify associated genes and variants. This retrospective multicentre cohort study covers fetuses sequenced after a non-diagnostic chromosomal microarray, with clinical data drawn from prenatal ultrasound and fetal MRI reports, and cases classified as isolated ACC, ACC with additional central nervous system abnormalities, or ACC with extracranial abnormalities; variants were classified using ACMG or ACGS criteria. Among 321 fetuses, a pathogenic or likely pathogenic variant is identified in 97 cases (30.2%), with yield rising with phenotypic complexity: 17.3% in isolated ACC, 25.7% with additional central nervous system abnormalities and 41.0% with extracranial abnormalities. MRI confirmation, available in 249 cases (77.6%), does not alter the overall yield, and no significant difference is seen between complete ACC and other ACC types; 51 genes carry pathogenic or likely pathogenic variants, TUBA1A being the most frequent.

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

The yield gradient by phenotypic complexity gives prenatal counselling a usable order of magnitude, and a yield of 17.3% even in isolated ACC argues against restricting sequencing to complex forms. That MRI confirmation, available in 77.6% of cases, did not modify the overall yield suggests that it depends chiefly on the presence of associated anomalies rather than on imaging confirmation of the ACC. This is, however, a retrospective cohort whose abstract describes neither recruitment procedures nor pregnancy outcomes, which prevents translating these yields into prognosis.

Analysis by Dr Thibaut Benquey