In INSIGNIA we are seeking to identify, characterise and curate signatures of mutagenesis in somatic cells from patients with genetic disorders associated with DNA repair or replication pathways. We are also interested to recruit patients who have had a history of exposure to any kind of chemical mutagen.

If you have patients that you think would be eligible for this study and would like to find out more about INSIGNIA, please use the links below.

Patient Eligibility

We are seeking patients with genetic disorders associated with DNA repair or replication pathways, or who have a history of exposure to any kind of chemical mutagen.

Inclusion Criteria:

  • Known DNA repair/replication syndrome
  • Unknown but suspected DNA repair/replication defect with at least two of the following features:
    • Progeroid symptoms
    • Early-onset malignancy
    • Growth retardation
    • Photosensitivity
    • Marrow/Immune deficiency
    • Developmental delay/neurodegeneration
  • Exposure to known carcinogen in adulthood or childhood e.g. Chernobyl/Japan radiation exposure, occupational exposures such as benzene.
  • Exposure to chemical mutagen in utero. e.g. Embryopathies such as fetal alcohol syndrome, retinoid acid exposure, fetal cocaine syndrome, fetal exposure to varicella or other infection.

Exclusion Criteria:

  • Over 80

What Is Required For The Study?

  • Participants will need to be consented by the recruiting clinician prior to participation.
  • Two blood samples will be requested from each participant, one for germline DNA and one for generating induced pluripotent stem (iPS) cells.
  • On rare occasions a skin or saliva sample may be required.
  • A clinical proforma will be completed by the recruiting clinician to provide detailed information on the health status of the participant.
  • The study protocol outlines the processes involved in more detail.

What Does The Study Offer?

For each participant INSIGNIA includes:

  • Whole genome sequencing of the germline DNA
  • Generation of a stock of erythroblast-derived iPS cells
  • Whole genome sequencing of iPS cell clone and/or subclones
  • Whole genome analyses of somatic mutation data: integrative substitution, indel, copy number and rearrangement data
  • Comparative expression and methylation analyses

The primary aim of performing whole genome sequencing of the patient germline DNA is to allow the background 'normal' variations to be identified. These will then be subtracted from the whole genome sequence of the iPS cell clones in order to obtain a catalogue of somatic mutations.

Whole genome sequencing of the patient germline will also enable unconfirmed diagnoses to be sought. However, germline variation will not be analysed unless specifically requested.

Study Ethics

This research study has been reviewed by a group of people called a research ethics committee (REC), to protect the interests of participants in the study.

  • INSIGNIA has been reviewed by and received a favorable ethical opinion from the NRES Committee East of England - Norfolk (Reference 13/EE/0302).
  • To ensure compliance with the Adults with Incapacity (Scotland) Act 2000, INSIGNIA has also been reviewed and received a favorable ethical opinion from Scotland A REC (Reference 14/SS/0096).
  • The Office for Research Ethics Committees Northern Ireland (ORECNI) has approved the participant information sheets and consent forms pertaining to adults with incapacity for use in Northern Ireland.

This study has also been reviewed by Research and Development (R&D) departments at NHS Trusts involved in the study.

  • R&D approval has been received from the lead NHS site (Cambridge University Hospitals; Reference A092892).
  • R&D approval from additional NHS Trusts has been sought under the terms of the NIHR UK Rare Genetic Disease Research Consortium Agreement, the Musketeers Memorandum.
  • Further information on the Musketeers Memorandum.
  • For participating NHS Trusts that are not part of the Musketeers Memorandum, individual R&D approval has been sought.
  • INSIGNIA is sponsored by Genome Research Ltd.

UK Clinical Research Network

Further Information

Participant information sheets and consent forms can be found under Further Information.

Publications providing more detailed information on research into mutational signatures can also be found under Further Information.


Cookies policy | Terms & Conditions. This site is hosted by the Wellcome Sanger Institute