Exome sequencing for perinatal phenotypes: The significance of deep phenotyping

To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization.

A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES.

In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies.

Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.