Studying patients with deficiencies in DNA replication/repair
Research type
Research Study
Full title
A research based approach to genetically diagnose patients with deficiencies in DNA replication/repair
IRAS ID
249996
Contact name
Birgit Whitman
Contact email
Sponsor organisation
University of Birmingham
Clinicaltrials.gov Identifier
N/A, N/A
Duration of Study in the UK
10 years, 0 months, 0 days
Research summary
For over 20 years we have developed an expertise in understanding the cellular processes involved in recognising and repairing DNA damage. Much of this expertise has stemmed from our long-standing interest in the rare human genome instability disorder Ataxia-Telangiectasia (A-T), which is caused by mutations in the ATM gene. As a consequence of this, we have been recognised, through the National Specialised Commissioning Group of the NHS, as the National Laboratory for genetic confirmation of the clinical diagnosis of A-T and A-T related disorders e.g. A-T-like disorder (ATLD) and ataxia oculomotor apraxia (AOA) types 1 and 2.
We often receive samples from patients who turn out not to be A-T/A-T like disorder, but who exhibit some clinical symptoms consistent with other known DNA repair/replication disorders e.g. they have short stature and microcephaly (small head and brain), skeletal abnormalities and/or have immunodeficiency. In these circumstances, it is our role to investigate any potential underlying DNA repair and/or replication defect and hopefully provide a diagnosis.
For a significant proportion of samples we receive, we cannot obtain a clear immediate genetic diagnosis, and longer term studies therefore need to be carried out. These may include whole exome sequencing of patient cells to identify the underlying genetic cause of the disease, as well as functional analysis of DNA replication and repair pathways using cell lines established from patient blood and/or skin sample. Using these approaches, we have previously identified several novel human disorders associated with defective DNA repair and/or replication e.g. RIDDLE syndrome, Microcephalic Dwarfism linked with mutations in either TRAIP or DONSON. This aim of this study is to use a combination of whole exome sequencing and functional analysis of DNA repair/replication to identify the underlying genetic defect(s) in a number of undiagnosed patients who exhibit clinical/cellular symptoms consistent with defective DNA repair/replication.
REC name
West Midlands - Coventry & Warwickshire Research Ethics Committee
REC reference
20/WM/0098
Date of REC Opinion
1 Jun 2020
REC opinion
Further Information Favourable Opinion