Lessons learnt from prenatal exome sequencing

Area of Science:

• Genetics
• Prenatal Diagnosis
• Bioinformatics

Background:

• Prenatal exome sequencing (ES) is increasingly used for diagnosing monogenic disorders in fetuses with structural anomalies.
• A national trio ES service in England utilizes a 1205-gene panel to minimize incidental findings and focus variant analysis.
• This review examines early experiences with ES service delivery, focusing on interpretation and reporting challenges.

Purpose of the Study:

• To review early laboratory experiences with prenatal exome sequencing (ES) service delivery.
• To identify challenges in variant interpretation and reporting within a national ES program.
• To inform future development and optimization of prenatal diagnostic services.

Main Methods:

• Retrospective review of laboratory records for completed prenatal exome sequencing cases.
• Analysis of cases identified as challenging, including those with interpretation difficulties, missed diagnoses due to inheritance filtering, and lack of prenatal diagnosis.
• Inclusion of cases with copy number variants not detectable by standard microarray analysis.

Main Results:

• Out of 116 completed cases, 24 presented challenges, including 13 with analysis/reporting difficulties.
• Trio inheritance filtering would have missed diagnoses in nine cases.
• Two cases lacked a prenatal diagnosis due to pipeline sensitivity or the causative gene not being on the panel; two copy number variant cases were missed by microarray.

Conclusions:

• Accurate variant interpretation necessitates close collaboration between referring clinicians and laboratory staff.
• Inheritance filtering can miss approximately 5% of diagnoses, and panel analysis does not eliminate incidental findings.
• Continuous review of scientific literature is crucial for classifying variants and improving diagnostic accuracy.