Identification of New Candidate Genes in Patients With Mitochondrial Disease by High Resolution Chromosome Analysis on DNA Chip
Identification of New Candidate Genes in Patients With Mitochondrial Disease by High Resolution Chromosome Analysis on DNA Chip
Mitochondrial diseases are complex diseases with great clinical and genetic heterogeneity and
 their diagnosis is difficult.

 The Medical Genetics Department includes among its activities the diagnosis of these
 diseases. It has been a reference centre for mitochondrial diseases at the national level
 since 2006 and was recently approved under the call for projects "European Reference Network
 (ERN) for rare diseases", EURO-NMD, supported by the Nice University Hospital. The routine
 diagnostic strategy is based on high throughput mitochondrial DNA (mtDNA) sequencing analysis
 and a panel of 281 targeted "mitochondriopathies" genes. When these analyses are negative, an
 exome analysis (high throughput sequencing of all exons in the genome) can be performed in a
 research setting. To date, about 40% of the patients analysed remain without genetic
 diagnosis. Indeed, it does not allow to identify large variations of deletion, duplication or
 CNV (copy number variation) type. Moreover, targeting only exons, exome sequencing does not
 allow the detection of intronic or localized mutations in regulatory regions.

 The identification of CNVs is made possible by chromosomal analysis on a DNA chip (CADC).
 This recognized technique is used routinely in the laboratory. The investigators use chips
 with a minimum resolution of approximately 13Kb for the genome-wide study of CNVs in patients
 with developmental disorders. However, this resolution is insufficient to detect rework
 events of the order of magnitude of an exon. There are high-resolution DNA chips, compatible
 with our platform, that would allow the investigators to more accurately visualize smaller
 rearrangements that could not be identified by exome analysis. The combined exome/CADC
 strategy has already proven its effectiveness in diagnosing various diseases by increasing
 yield.

 In this context, the investigators aim to use this strategy in this non-interventional study
 on a series of 15 patients with mitochondrial disease who remain undiagnosed after analysis
 of mtDNA, gene panel and exome. They will test 2 types of patients:

 -  In the first series, whose disease is supposed to be transmitted in an autosomal
 recessive mode, only one heterozygous variant was identified in a gene already described
 in a comparable clinical picture. It is therefore possible that these patients are
 carriers on the second allele of a CNV, which the exome sequencing could not identify.

 -  In the second series, the exome analysis did not allow the identification of a single
 responsible gene (several candidate genes without any certainty on the pathogenicity of
 the gene(s) or variant(s))
Inclusion Criteria:

 -  Patients with mitochondrial disease (clinical and histological criteria)

 -  Or Patients for whom an exome analysis has been performed, who are carriers of a
 pathogenic or probably pathogenic variant, in a heterozygous state, in an autosomal
 recessive transmission gene strongly candidate in view of the patient's clinic.

 -  Or patients for whom exome analysis did not reveal any pathogenic variant explaining
 the phenotype

 Exclusion Criteria:

 -  People hospitalized without consent;

 -  Phenotype not suggestive of mitochondrial disease