Biomarkers for genome instability in some genetic disorders: a pilot study

Abstract

Context: The study of genome integrity in some genetic disorders has diagnostic and prognostic importance because of the evident relationship between genome instability and both DNA repair deficiencies and cancer predisposition.

Objective: The objective was to compare the chromosomal and DNA damage responses in lymphocytes from patients with Nijmegen breakage syndrome (NBS), Fanconi anemia (FA) and Williams–Beuren syndrome (WBS) to find additional biomarkers of genome instability.

Methods: The cytogenetic approaches were combined with the alkaline Comet assay to estimate genome integrity in cultured or freshly isolated and H₂O₂-treated lymphocytes.

Results: Basal frequencies of chromosome aberrations were significantly increased in NBS/FA probands and NBS heterozygous carriers. The NBS diagnosis was confirmed by detecting site-specific rearrangements, while the mitomycin C (MMC)-stress test was highly positive in a FA patient. Among patients with suspected WBS, 12 individuals had a 7q11.23 microdeletion. In the Comet assay, genome instability was revealed in all three disorders, impaired capacity to repair oxidative damage being observed in NBS and WBS in contrast to FA and controls.

Conclusion: The results indicate that the estimates of DNA damage response may be proposed as efficient biomarkers for detecting and characterizing genome instability in the genetic disorders under study.

Keywords::

• Genome instability
• chromosome aberrations
• DNA damage
• DNA repair
• genetic disorders

Acknowledgements

The authors are grateful to Professor Irena Szumiel, DSc (Center of Radiobiology & Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Poland) and to Dr. Gregory Nikiforovich, DSc (MolLife Design LLC, St. Louis, USA) for critical reading of the manuscript and helpful remarks as well as to Boris Anoshenko, PhD (the Central Botanical Garden, the National Academy of Sciences of Belarus) for assistance with statistical analysis of the data. The authors express sincere gratitude to the Presidents of the Association “Enfants de Tchernobyl Belarus” (France), Professor Michel Fernex and Yves Lenoir for support of investigations of genome instability in the Belarusian population.

Declaration of interest

The authors report no conflict of interest.