The diagnostic efficacy of exome data analysis using fixed neurodevelopmental gene lists: implications for prenatal setting.

OBJECTIVE Laboratories performing prenatal exome sequencing (ES) frequently limit analysis to predetermined gene lists. We used a diagnostic postnatal ES cohort to assess how many of the genes diagnosed are not included in a number of select fixed lists used for prenatal diagnosis. METHODS Of 601 postnatal ES tests, pathogenic variants related to neurodevelopmental disorders were detected in 138 probands. We evaluated if causative genes were present in the following: (1) Developmental Disorders Genotype-Phenotype Database (DDG2P) list, (2) a commercial laboratory list for prenatal ES, (3) The PanelApp Fetal anomalies panel, and (4) a published list used for prenatal diagnosis by ES (PAGE study). RESULTS The percentages of cases where the diagnosed gene was not included in the selected four lists were ; 11.6 %, 17.24%, 23.2%, and 10.9%, respectively. In 13/138 (9.4%) cases, the causative gene was not included in any of the lists; in 4/13 (∼ 30%) cases non-inclusion was explained by a relatively recent discovery of gene-phenotype association. CONCLUSIONS A significant number of genes related to neurocognitive phenotypes are not included in some of the lists used for prenatal ES data interpretation. These are not only genes related to recently discovered disorders, but also genes with well-established gene-phenotype. This article is protected by copyright. All rights reserved. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Laboratories performing prenatal exome sequencing (ES) frequently limit analysis to predetermined gene lists. We used a postnatal ES cohort to assess how many of the genes diagnosed in this cohort are not included in selected fixed lists . WHAT DOES THIS STUDY ADD?: A significant number of genes related to neurocognitive phenotypes are not included in curated lists. This results from non-inclusion of recently discovered disorders, as well as disorders with well-established gene-phenotype associations.