Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases

Morgane Plutino,Véronique Paquis-Flucklinger,Sylvie Bannwarth,Konstantina Fragaki,Samira Ait-El-Mkadem,Annabelle Chaussenot,Cécile Rouzier

doi:10.1186/s12881-018-0568-y

Abstract

BackgroundSince the advent of next generation sequencing (NGS), several studies have tried to evaluate the relevance of targeted gene panel sequencing and whole exome sequencing for molecular diagnosis of mitochondrial diseases. The comparison between these different strategies is extremely difficult. A recent study analysed a cohort of patients affected by a mitochondrial disease using a NGS approach based on a targeted gene panel including 132 genes. This strategy led to identify the causative mutations in 15.2% of cases. The number of novel genes responsible for respiratory chain deficiency increases very rapidly.MethodsIn order to determine the impact of larger panels used as a first screening strategy on molecular diagnosis success, we analysed a cohort of 80 patients affected by a mitochondrial disease with a first mitochondrial DNA (mtDNA) NGS screening and secondarily a targeted mitochondrial panel of 281 nuclear genes.ResultsPathogenic mtDNA abnormalities were identified in 4.1% (1/24) of children and 25% (14/56) of adult patients. The remaining 65 patients were analysed with our targeted mitochondrial panel and this approach enabled us to achieve an identification rate of 21.7% (5/23) in children versus 7.1% (3/42) in adults.ConclusionsOur results confirm that larger gene panels do not improve diagnostic yield of mitochondrial diseases due to (i) their very high genetic heterogeneity, (ii) the ongoing discovery of novel genes and (iii) mutations in genes apparently not related to mitochondrial function that lead to secondary respiratory chain deficiency.

Highlights

Since the advent of generation sequencing (NGS), several studies have tried to evaluate the relevance of targeted gene panel sequencing and whole exome sequencing for molecular diagnosis of mitochondrial diseases
The m.1555A > G mutation was found in a 15 year-old patient (N°24) presenting with a pseudo-stroke episode associated with Fahr syndrome
A 31 year-old patient (N°30) had an optic neuropathy associated with the m.3460G > A pathogenic variant

Summary

Introduction

Since the advent of generation sequencing (NGS), several studies have tried to evaluate the relevance of targeted gene panel sequencing and whole exome sequencing for molecular diagnosis of mitochondrial diseases The comparison between these different strategies is extremely difficult. A recent study analysed a cohort of patients affected by a mitochondrial disease using a NGS approach based on a targeted gene panel including 132 genes This strategy led to identify the causative mutations in 15.2% of cases. Deficiency of the mitochondrial RC is responsible for the lack of ATP production, which provides energy in each cell through oxidative phosphorylation (OXPHOS) The diagnosis of such diseases is challenging because of extreme phenotypic heterogeneity, variable age of onset and different modes of inheritance. Encephalopathy, epilepsy, cerebellar ataxia, axonal neuropathy, migraine, stroke-like episodes, cognitive impairment and movement disorders are mainly found in patients presenting with neurological symptoms

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Discussion

Conclusion