title: 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.
authors.affiliation: IRCAN, CNRS UMR 7284/Inserm U1081/UNS, Faculté de Médecine, Nice, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Lebre
authors.forename: Claude
authors.initials: C
authors.lastname: Jardel
authors.forename: Annabelle
authors.initials: A
authors.lastname: Chaussenot
authors.forename: Claire
authors.initials: C
authors.lastname: Hoarau
authors.forename: Hassani
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authors.lastname: Maoulida
authors.forename: Nathanaël
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authors.lastname: Charrier
authors.forename: Xiaowu
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authors.lastname: Gai
authors.forename: Hongbo M
authors.initials: HM
authors.lastname: Xie
authors.forename: Marc
authors.initials: M
authors.lastname: Ferre
authors.forename: Konstantina
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authors.lastname: Fragaki
authors.forename: Gaëlle
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authors.lastname: Hardy
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mousson de Camaret
authors.forename: Sandrine
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authors.lastname: Marlin
authors.forename: Claire Marie
authors.initials: CM
authors.lastname: Dhaenens
authors.forename: Abdelhamid
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authors.lastname: Slama
authors.forename: Christophe
authors.initials: C
authors.lastname: Rocher
authors.forename: Jean
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authors.lastname: Paul Bonnefont
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Nadia
authors.initials: N
authors.lastname: Aoutil
authors.forename: Mylène
authors.initials: M
authors.lastname: Gilleron
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ceresuela
authors.forename: Laurence
authors.initials: L
authors.lastname: Jonard
authors.forename: Aurore
authors.initials: A
authors.lastname: Devos
authors.forename: Caroline
authors.initials: C
authors.lastname: Espil-Taris
authors.forename: Delphine
authors.initials: D
authors.lastname: Martinez
authors.forename: Pauline
authors.initials: P
authors.lastname: Gaignard
authors.forename: Kim-Hanh
authors.initials: KH
authors.lastname: Le Quan Sang
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.forename: Catherine
authors.initials: C
authors.lastname: Florentz
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand-Zaleski
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: Mitochondrial DNA; Mitochondrial disease; Patient cohort; Rare mutations