Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility?

Area of Science:

• Genetics
• Prenatal Diagnosis
• Medical Diagnostics

Background:

• Congenital anomalies in fetuses pose diagnostic challenges.
• Prenatal exome sequencing (pES) shows promise but requires evaluation of its impact on ongoing pregnancies.
• Previous studies primarily focused on diagnostic yield, not clinical prediction.

Purpose of the Study:

• To assess if prenatal molecular diagnosis reliably predicts unborn child's clinical features.
• To determine the gestational age for sufficient ultrasound findings to support pES variant pathogenicity.

Main Methods:

• Retrospective analysis of 47 cases with ultrasound anomalies undergoing exome sequencing (ES).
• Blinded reanalysis of ES data using only prenatal features.
• Correlation with complete clinical assessment and follow-up.

Main Results:

• Standard ES achieved molecular diagnosis in 43% of cases.
• Blinded reanalysis enabled retrospective prenatal diagnosis in 95% of diagnosed cases.
• Ultrasound findings supported molecular diagnosis by a mean gestational age of 22+5 weeks; syndromic presentation confirmed in 21/23 newborns and all terminated pregnancies.

Conclusions:

• pES is a valuable tool for identifying genetic causes of fetal congenital malformations.
• pES results generally predict the postnatal phenotype accurately.
• Prenatal diagnosis requires specific approaches, and negative pES results are not fully reassuring.