Exome sequencing for structurally normal fetuses-yields and ethical issues.

Area of Science:

• Medical Genetics
• Prenatal Diagnosis
• Genomic Medicine

Background:

• Chromosomal microarray analysis (CMA) has a known diagnostic yield in structurally normal fetuses, ranging from 0.4% to 1.4%.
• The incremental diagnostic value of exome sequencing (ES) in this specific population remains to be fully elucidated.
• Advances in next-generation sequencing technologies necessitate re-evaluation of diagnostic strategies in prenatal settings.

Purpose of the Study:

• To determine the additional diagnostic yield of exome sequencing (ES) in fetuses with normal ultrasound findings.
• To compare the efficacy of ES against established methods like CMA for detecting pathogenic genetic variants.
• To assess the implications of ES findings for genetic counseling and prenatal care.

Main Methods:

• Retrospective analysis of 1,526 fetal exome sequencing cases performed between February 2017 and April 2022.
• Focus on a subset of 482 fetuses with structurally normal ultrasound examinations.
• Reporting of pathogenic and likely pathogenic (P/LP) variants according to ACMG classification, including childhood-relevant secondary findings.

Main Results:

• Four out of 482 (0.8%) structurally normal fetuses had P/LP variants associated with moderate to severe conditions (Wilson disease, Enhanced S-cone syndrome, Legius syndrome, Muenke syndrome).
• Two additional fetuses had clinically relevant secondary findings.
• The overall detection rate of significant findings via ES in this cohort underscores its utility beyond CMA.

Conclusions:

• Relying solely on CMA for structurally normal fetuses may lead to missed diagnoses and false reassurance.
• Prenatal exome sequencing offers a higher diagnostic yield, identifying significant genetic conditions.
• Comprehensive genetic testing, including ES, requires careful management, restrictive analysis protocols, and robust pre- and post-test genetic counseling.