Prenatal Exome Sequencing for Fetal Macrocephaly: A Large Prospective Observational Cohort Study

Area of Science:

• Genetics
• Fetal Medicine
• Genomic Medicine

Background:

• Macrocephaly, defined as head circumference ≥ +2 SD, is a common fetal anomaly.
• Chromosomal microarray (CMA) has limitations in diagnosing the underlying causes of macrocephaly.
• Exome sequencing (ES) offers a more comprehensive genetic analysis.

Purpose of the Study:

• To evaluate the diagnostic performance of trio-exome sequencing (ES) in macrocephalic fetuses with previously normal CMA results.
• To identify specific clinical features associated with a higher diagnostic yield of ES.

Main Methods:

• Retrospective analysis of trio-exome sequencing data from 87 macrocephalic fetuses with negative CMA results.
• Subgroup analyses based on gestational age, head circumference Z-scores, presence of anomalies, and growth parameters.
• Systematic review of molecular diagnoses and affected signaling pathways.

Main Results:

• Trio-ES established molecular diagnoses in 39.1% (34/87) of cases.
• The diagnostic yield was significantly higher in non-isolated macrocephaly (65.0%) versus isolated cases (17.0%).
• Higher yields were observed with earlier diagnosis (<32 weeks), higher HC Z-scores (≥+3 SD), micromelia, and absence of large-for-gestational-age.

Conclusions:

• Exome sequencing substantially increases the detection rate of monogenic disorders in macrocephalic fetuses compared to CMA.
• Specific clinical features like micromelia and ventriculomegaly are key indicators for genetic diagnoses.
• These findings are vital for accurate prenatal diagnosis, counseling, and management of macrocephalic fetuses.