Lessons learnt from prenatal exome sequencing

Abstract

Background Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service delivered from two laboratories. To minimise incidental findings and reduce the number of variants investigated, analysis uses a panel of 1205 genes where pathogenic variants may cause abnormalities presenting prenatally. Here we review our laboratory's early experience developing and delivering ES to identify challenges in interpretation and reporting and inform service development. Methods A retrospective laboratory records review from 01.04.2020 to 31.05.2021. Results Twenty‐four of 116 completed cases were identified as challenging including 13 resulting in difficulties in analysis and reporting, nine where trio inheritance filtering would have missed the diagnosis, and two with no prenatal diagnosis; one due to inadequate pipeline sensitivity, the other because the gene was not on the panel. Two cases with copy number variants identified were not detectable by microarray. Conclusions Variant interpretation requires close communication between referring clinicians, with occasional additional examination of the fetus or parents and communication of evolving phenotypes. Inheritance filtering misses ∼5% of diagnoses. Panel analysis reduces but does not exclude incidental findings. Regular review of published literature is required to identify new reports that may aid classification.

Family history is key to the interpretation of exome sequencing in the prenatal context: unexpected diagnosis of Basal Cell Nevus Syndrome

“…Prenatal diagnosis may thus take great advantage of genotype‐first approaches although a definitive prenatal molecular diagnosis can only be reached if a robust correlation with the phenotype can be established. In accordance with others, 31 this case also stresses the importance of careful examination of (likely) pathogenic variants in dominant genes, even if inherited from apparently healthy parents.…”

“…Prenatal robust correlation with the phenotype can be established. In accordance with others, 31 this case also stresses the importance of careful examination of (likely) pathogenic variants in dominant genes, even if inherited from apparently healthy parents.…”

Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation

“…Clinical diagnostic yield was relatively low at 10–12% overall. Selection of cases using a ‘pre-test’ multidisciplinary team (including a Clinical Geneticist) and careful ‘targeting’ of specific fetal phenotypes may significantly increase diagnostic rate to over 30% [ 4 , 5 , 6 ].…”

Prenatal exomes and genomes – so much new and so much more to learn

“…Strategies for analyzing data, such as inheritance filtering, can limit the results obtained. 23 Two studies compare results from sequencing on neonates to what could have been detected prenatally if we had more access to sequencing and better strategies to analyze the data and show that many conditions could be diagnosed earlier. 24,25 Moreover, at least one study showed that even for fetuses with no observable structural anomalies, P and LP variants can be detected.…”

“…Finally, our tools and knowledge to gain all the potential benefits from sequencing are still incomplete. Strategies for analyzing data, such as inheritance filtering, can limit the results obtained 23 . Two studies compare results from sequencing on neonates to what could have been detected prenatally if we had more access to sequencing and better strategies to analyze the data and show that many conditions could be diagnosed earlier 24,25 .…”