Exome re-analysis driven by deep phenotyping increases diagnostic yield

Abstract

ObjectiveTo explore if clinician driven systematic reanalysis of "negative" exome sequencing data of patients with a strong suspicion of a Mendelian disease by a Clinical Geneticist using deep phenotyping can increase the diagnostic yield. MethodsTen patients were deep phenotyped using Gestalt matching (Face2Gene) and OMIM database searching (Phenomizer) to build a list of candidate genes of interest. The Variant Call Format (vcf) files for individual patients were obtained from the sequencing laboratory and reanalyzed in the wANNOVAR server. The annotated list of variants was queried for the genes of interest. Copy number variant analysis was performed using ExomeDepth (v1.1.10) R package. ResultsA homozygous pathogenic mutation in the NPHP3 gene (c.2805C>T) was identified in one child with Renal-Hepatic-Pancreatic Dysplasia and a multiexon deletion in the CUL7 gene was identified in another child with 3M syndrome. ConclusionsSystematic re-analysis of exome sequencing data by a Clinical Geneticist can increase the diagnostic yield with minimal additional cost.