New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centreReportar como inadecuado

New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Translational Medicine

, 14:174

Disease biomarkers


BackgroundWhole-exome sequencing WES has led to an exponential increase in identification of causative variants in mitochondrial disorders MD.

MethodsWe performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family.

ResultsLikely causative mutations were identified in 67 59.3 % patients; these included variants in mtDNA 6 patients and nDNA: X-linked 9 patients, autosomal dominant 5 patients, and autosomal recessive 47 patients, 11 homozygotes. Novel variants accounted for 50.5 % 50-99 of all detected changes. In 47 patients, changes in 31 MD-related genes ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2 were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general-ethnic prevalence. In 19 cases, variants in 18 non-MD related genes ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria MDC scale from 36 to 90 % for low and high probability, respectively. The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood from 20 to 97 %. Molecular diagnosis was established in 30-47 63.8 % neonates and in 17-28 60.7 % patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria 3-MGA as a discriminative feature. New MD-related candidate gene NDUFB8 is under verification.

ConclusionsWe suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.

KeywordsWhole-exome sequencing Mitochondrial disorders Mitochondrial disease criteria scale Neonates Basal ganglia involvement Leigh syndrome 3-methylglutaconic aciduria Novel mutation Candidate gene AbbreviationsMDmitochondrial disorders

WESwhole-exome sequencing

MDCmitochondrial disease criteria

NGSnext generation sequencing

LA-urialactic aciduria

3-MGA-uria3-methylglutaconic aciduria

nDNAnuclear DNA

Dorota Piekutowska-Abramczuk, Elżbieta Ciara and Joanna Trubicka contributed equally to this work

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-016-0930-9 contains supplementary material, which is available to authorized users.

Download fulltext PDF

Autor: Ewa Pronicka - Dorota Piekutowska-Abramczuk - Elżbieta Ciara - Joanna Trubicka - Dariusz Rokicki - Agnieszka Karkucińska-W


Documentos relacionados