Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.

NCT05615571 | Completed

• 1 other identifier: CHUBX 2017/38
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous. The diagnosis is based on brain MRI. It is also based on genetic testing. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted. Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; on the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.

Conditions

Neurodegeneration With Brain Iron Accumulation (NBIA)

Outcome Measures

Primary Outcomes (2)

• Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.

  Records of coverage (% of designed regions)

  through study completion, an average of 2 years

• Sequencing tests of a panel of 22 genes using a dedicated custom capture and a medium throughput sequencing protocol.

  Records of depth of sequencing (reads number)

  through study completion, an average of 4 years

Secondary Outcomes (2)

• Identification of the dominant form using biochemical analysis in patient's fibroblasts

  through study completion, an average of 2 years

• Identification of the dominant form using biochemical analysis in patient's fibroblasts

  through study completion, an average of 2 years

Study Arms (2)

Patients with NBIA who remain without molecular diagnosis

A group of 40 patients with NBIA, who remain without molecular diagnosis

Genetic: Sequencing tests

Patients with NBIA with identified mutations in genes

A group of patients with 2 frequent forms of NBIA, carrying mutations in genes (already studied in the CHU molecular diagnostic laboratory)

Genetic: Establishment of mitochondrial markers

Interventions

Establishment of mitochondrial markers GENETIC

Establishment of mitochondrial markers from fibroblasts in culture, obtained from a skin biopsy. Establishment of yeast models to show biochemical mitochondrial alterations: introduction of missense variants in the pantothenate kinase yeast gene Cab1 whose deletion is lethal, followed by growth of mutant strains on fermentation and respiratory media.

Patients with NBIA with identified mutations in genes

Sequencing tests GENETIC

sequencing tests of a panel of 22 genes (9 already known and 13 new genes) using a dedicated custom capture and a medium throughput sequencing protocol.

Patients with NBIA who remain without molecular diagnosis

Eligibility Criteria

• Sex: all
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with NBIA

You may qualify if:

• NBIA Patients diagnosed with a pathogenic variation or any variation that could impact gene function (class 4 or 5 according to ACMG criteria) in the following genes: C19ORF12, PANK2, PLA2G6, DCAF17, FA2H, WDR45, FTL, CP and ATP13A2 and whose fibroblasts have been collected at Bordeaux University Hospital for functional analysis during the diagnosis procedure
• NBIA patients without conclusive testing in none of these nine genes and whose DNA has been collected during the diagnosis procedure at Bordeaux University Hospital

You may not qualify if:

• Patients without imaging (MRI or scan) signs of NBIA
• Patients without french healthcare insurance

Sponsors & Collaborators

• University Hospital, Bordeaux: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (1)

Centre Hospitalier Universitaire de Bordeaux

Talence, France

Location

Related Publications (1)

• Angelini C, Durand CM, Fergelot P, Deforges J, Vital A, Menegon P, Sarrazin E, Bellance R, Mathis S, Gonzalez V, Renaud M, Frismand S, Schmitt E, Rouanet M, Burglen L, Chabrol B, Desnous B, Arveiler B, Stevanin G, Coupry I, Goizet C. Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes. Mov Disord. 2023 Nov;38(11):2103-2115. doi: 10.1002/mds.29576. Epub 2023 Aug 21.

  PMID: 37605305 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

cutaneous biopsy and blood samples

MeSH Terms

Conditions

Pantothenate Kinase-Associated Neurodegeneration

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroaxonal Dystrophies; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Patricia FERGELOT MAURIN

  University Hospital, Bordeaux

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2021
• First Posted: November 14, 2022
• Study Start: January 4, 2018
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: November 14, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)