6533b7d9fe1ef96bd126b9aa
RESEARCH PRODUCT
Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light
Bastien Le RouxGuy LenaersXavier ZanlonghiPatrizia Amati-bonneauFloris ChabrunThomas FoulonneauAngélique CaignardStéphanie LeruezPhilippe GohierDan MileaJohan Den DunnenPascal ReynierMarc FerréPhilippine GarretCéline BrisVincent ProcaccioPatrizia Amati‐bonneauPierre VabresNada HoucinatEmilie TisserantFrançois FeilletAnge‐line BruelVirginie QuéréChristophe PhilippeArthur SorlinFrédéric Tran Mau‐themAntonio VitobelloJean‐marc CostaAïcha BoughalemDetlef TrostLaurence FaivreChristel Thauvin‐robinetYannis Duffourdsubject
AdultMaleMitochondrial DNAAtaxiaAdolescentDevelopmental Disabilities[SDV]Life Sciences [q-bio]BiologyDNA MitochondrialGenomeHaplogroupYoung Adult03 medical and health sciencesExome SequencingGeneticsmedicineHumansChildExomeGenetics (clinical)Exome sequencingComputingMilieux_MISCELLANEOUSAged030304 developmental biologyAged 80 and overGenetics0303 health sciences030305 genetics & heredityInfant NewbornComputational BiologyGenetic VariationInfantMiddle AgedPhenotypeEarly DiagnosisChild PreschoolFemaleNervous System Diseasesmedicine.symptomdescription
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 the mtDNA genome on a large unspecific cohort 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 out of 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 out of 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-11-23 |