Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

Elias L Salfati,Jonathan R Lucas,Eric J Topol,Ali Torkamani,Glenn N Wagner,Evan D Muse,Emily G Spencer,Steven Campman,Sarah E Topol,Manuel Rueda

doi:10.1186/s13073-019-0702-2

Elias L Salfati, Jonathan R Lucas + Show 8 more

Open Access

https://doi.org/10.1186/s13073-019-0702-2

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Abstract

BackgroundWhole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis.MethodsOf the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest.ResultsInitial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively.ConclusionsThe basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

Highlights

Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death
Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%)
A total of 577 variants were considered for further analysis by our variant annotation and filtering workflows across both Idiopathic Diseases of Human (IDIOM) and Molecular Autopsy (MA) studies, an average of ~ 5.3 variants per subject (Additional file 1: Table S1 and Table S2)

Summary

Introduction

Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. We report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Sudden unexplained death and rare undiagnosed disorders have major impacts on affected individuals as well as their family members. Whole-exome sequencing (WES) is a powerful approach for the identification of these genetic risk factors. The diagnostic yield of exome sequencing ranges from 15 to 50% depending upon the stringency of inclusion criteria and phenotype in question [3,4,5,6]. Even in cohorts most stringently recruited and most enriched with likely monogenic conditions, significant gaps remain in achieving expected diagnostic yield

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