Dataset Information

Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders.

ABSTRACT: BACKGROUND: Mitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5-40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known. METHODS: We analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both heteroplasmic and homoplasmic variants were identified using two complementary strategies (Surveyor and MitoChip). Multiple correspondence analyses followed by hierarchical ascendant cluster process were used to explore relationships between clinical spectrum, age at onset and localisation of mutations. RESULTS: 7.4% of deleterious mutations and 22.4% of novel putative mutations were identified. Pathogenic heteroplasmic mutations were more frequent than homoplasmic mutations (4.6% vs 2.8%). Patients carrying deleterious mutations showed symptoms before 16 years of age in 67% of cases. Early onset disease (<1 year) was significantly associated with mutations in protein coding genes (mainly in complex I) while late onset disorders (>16 years) were associated with mutations in tRNA genes. MTND5 and MTND6 genes were identified as 'hotspots' of mutations, with Leigh syndrome accounting for the large majority of associated phenotypes. CONCLUSIONS: Rare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency. This study shows that a comprehensive analysis of mtDNA is essential, and should include young children, for an accurate diagnosis that is now accessible with the development of next generation sequencing technology.

SUBMITTER: Bannwarth S

PROVIDER: S-EPMC3786640 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders.

Bannwarth Sylvie S Procaccio Vincent V Lebre Anne Sophie AS Jardel Claude C Chaussenot Annabelle A Hoarau Claire C Maoulida Hassani H Charrier Nathanaël N Gai Xiaowu X Xie Hongbo M HM Ferre Marc M Fragaki Konstantina K Hardy Gaëlle G Mousson de Camaret Bénédicte B Marlin Sandrine S Dhaenens Claire Marie CM Slama Abdelhamid A Rocher Christophe C Paul Bonnefont Jean J Rötig Agnès A Aoutil Nadia N Gilleron Mylène M Desquiret-Dumas Valérie V Reynier Pascal P Ceresuela Jennifer J Jonard Laurence L Devos Aurore A Espil-Taris Caroline C Martinez Delphine D Gaignard Pauline P Le Quan Sang Kim-Hanh KH Amati-Bonneau Patrizia P Falk Marni J MJ Florentz Catherine C Chabrol Brigitte B Durand-Zaleski Isabelle I Paquis-Flucklinger Véronique V

Journal of medical genetics 20130711 10

<h4>Background</h4>Mitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5-40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known.<h4>Methods</h4>We analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both hete ...[more]

PMID: 23847141

Similar Datasets

Project description:ObjectiveMitochondrial DNA (mtDNA) encodes the proteins of the electron transfer chain to produce adenosine triphosphate through oxidative phosphorylation, and is essential to sustain life. mtDNA is unique from the nuclear genome in so much as it is solely maternally inherited (non-mendelian patterning), and shows a relatively high rate of mutation due to the absence of error checking capacity. While it is generally assumed that most new mutations accumulate through the process of heteroplasmy, it is unknown whether mutations initiated in the mother are inherited, occur in utero, or occur and accumulate early in life. The purpose of this study is to examine the maternally heritable and de novo mutation rate in the fetal mtDNA through high-fidelity sequencing from a large population-based cohort.Study designSamples were obtained from 90 matched maternal (blood) and fetal (placental) pairs. In addition, a smaller cohort (n = 5) of maternal (blood), fetal (placental), and neonatal (cord blood) trios were subjected to DNA extraction and shotgun sequencing. The whole genome was sequenced on the Illumina HiSeq platform (Illumina Inc., San Diego, CA), and haplogroups and mtDNA variants were identified through mapping to reference mitochondrial genomes (NC_012920).ResultsWe observed 665 single nucleotide polymorphisms and 82 insertions-deletions variants identified in the cohort at large. We achieved high sequencing depth of the mtDNA to an average depth of 65X (range, 20-171X) coverage. The proportions of haplogroups identified in the cohort are consistent with the patient's self-identified ethnicity (>90% Hispanic), and all maternal-fetal pairs mapped to the identical haplogroup. Only variants from samples with average depth >20X and allele frequency >1% were included for further analysis. While the majority of the maternal-fetal pairs (>90%) demonstrated identical variants at the single nucleotide level, we observed rare mitochondrial single nucleotide polymorphism discordance between maternal and fetal mitochondrial genomes.ConclusionIn this first in-depth sequencing analysis of mtDNA from maternal-fetal pairs at the time of birth, a low rate of de novo mutations appears in the fetal mitochondrial genome. This implies that these mutations likely arise from the maternal heteroplasmic pool (eg, in the oocyte), and accumulate later in the offspring's life. These findings have key implications for both the occurrence and screening for mitochondrial disorders.

Dataset Information

Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders.

Publications

Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets