Deciphering exome sequencing data: bringing mitochondrial DNA variants to light.

Fiche publication

Date publication

août 2019


Human mutation


Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence, Pr PHILIPPE Christophe, Pr VABRES Pierre

Tous les auteurs :
Garret P, Bris C, Procaccio V, Bonneau PA, Vabres P, Houcinat N, Tisserant E, Feillet F, Bruel AL, Quéré V, Philippe C, Sorlin A, Mau-Them FT, Vitobello A, Costa JM, Boughalem A, Trost D, Faivre L, Thauvin-Robinet C, Duffourd Y


The expanding use of exome sequencing (ES) in diagnosis generates a huge amount of data, including untargeted mitochondrial DNA (mtDNA) sequences. We developed a strategy to deeply study ES data, focusing on mtDNA genome on a large unspecific cohort in order to increase diagnostic yield. A targeted bioinformatics pipeline assembled mitochondrial genome from ES data to detect pathogenic mtDNA variants in parallel with the "in-house" nuclear exome pipeline. MtDNA data coming from off-target sequences (indirect sequencing) were extracted from the BAM files in 928 individuals with developmental and/or neurological anomalies. The mtDNA variants were filtered out based on database information, cohort frequencies, haplogroups and protein consequences. Two homoplasmic pathogenic variants (m.9035T>C and m.11778G>A) were identified in 2/928 unrelated individuals (0.2%): the m.9035T>C (MT-ATP6) variant in a female with ataxia and the m.11778G>A (MT-ND4) variant in a male with a complex mosaic disorder and a severe ophthalmological phenotype, uncovering undiagnosed Leber's hereditary optic neuropathy (LHON). Seven secondary findings were also found, predisposing to deafness or LHON, in 7/928 individuals (0.75%). This study demonstrates the usefulness of including a targeted strategy in ES pipeline to detect mtDNA variants, improving results in diagnosis and research, without resampling patients and performing targeted mtDNA strategies. This article is protected by copyright. All rights reserved.

Mots clés

ES data, bioinformatics, mtDNA, pipeline


Hum. Mutat.. 2019 Aug 5;: