Identification of New Candidate Genes in Patients With Mitochondrial Disease by High Resolution Chromosome Analysis on DNA Chip (ACPA HR)

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))

Study Overview

• Status: Completed
• Conditions: Mitochondrial Diseases

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• France
  • Nice, France, 06000
    • Nice hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patient with mitochondrial deseases

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variation of Number of copies	The variations in the number of copies by quantitative Polymerase Chain Reaction (PCR) targeted on the region of interest, previously identified on the High Resolution Chromosome Analysis on DNA Chip (CADC), whether it is in copy loss or copy gain.	1 hour

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nice

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2020
• Primary Completion (Actual): March 20, 2022
• Study Completion (Actual): March 20, 2022

Study Registration Dates

• First Submitted: February 27, 2019
• First Submitted That Met QC Criteria: February 27, 2019
• First Posted (Actual): February 28, 2019

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Mitochondrial Diseases
• Other Study ID Numbers: 18-AOI-07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No