Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases.

Olivia V Poole,Cathy E Woodward,Nicholas Wood,Enrico Bugiardini,William L Macken,Michael G Hanna,Alan Pittman,David Murphy,Chiara Pizzamiglio,Rauan Kaiyrzhanov,Hallgeir Jonvik,Anthony A Amato,Vincenzo Salpietro,Allison Gregory,Micol Falabella,Robyn Labrum,Susan J Hayflick,Reza Maroofian,Henry Houlden,Queen Square Genomics ,Stéphanie Efthymiou ,Christopher Kobylecki ,Jana Vandrovcová ,Robert D S Pitceathly

doi:10.1002/ana.26063

Abstract

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty‐four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240–1247

Highlights

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES)
Significant Pathogenic Mitochondrial DNA Variants Clinically significant pathogenic mitochondrial DNA (mtDNA) variants were detected in 11 exomes from 9 unrelated families
Significant pathogenic mtDNA variants were detected in 11 exomes from 9 unrelated families, confirming an mtDNA-related primary mitochondrial diseases (PMDs) diagnosis in these patients

Summary

Introduction

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Twentyfour different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. The rapid expansion in recognized inherited neurological disorders has led to a “genetics first” approach to their diagnosis, which frequently involves the early application of clinical whole exome sequencing (WES).[1] There is growing evidence that the iterative re-analysis of exome data significantly improves the diagnostic yield of pathogenic DNA variants in rare diseases, and should be considered in all unresolved cases.[2]. We applied a Genome Analysis Toolkit (GATK) Mutect2-based[5,6] bioinformatics pipeline to analyze the mtDNA reads from 11,424 exomes, generated by University College London Queen Square Genomics Facility, and determined the diagnostic uplifts gained by including mtDNA analysis during the iterative reanalysis of neurological disease exomes

Methods

Results

Conclusion