The maintenance of genomic stability is a persistent challenge for all cells since their genomes are constantly exposed to damage from endogenous and exogenous agents that can lead to a continuous variety of chemical changes in nucleotides and breaks in the DNA strand. If these amendments are not appropriately repaired, they can destabilize the entire structure, resulting in genomic instability.
Defects in DNA repair mechanisms form the basis of genomic instability syndromes, or DNA repair syndromes, a spectrum of diseases that contain unique opportunities for studying the clinical consequences resulting from failures in genetic maintenance that can lead to premature aging and development of neoplasms.
Throughout the main instability syndromes, stands out the Bloom’s syndrome, a rare autosomal recessive chromosomal instability disorder whose main clinical manifestations are growth deficiency, telangiectasic facial erythema, photosensibility, immunodeficiency, and increased risk to develop neoplasms at an early age. The cells from patients display genomic instability characterized especially by increased sister chromatid exchanges (SCEs) due to mutations in the BLM gene, involved in the central role of genomic integrity maintenance.
The cytogenetic study, previously considered the gold standard diagnostic tool for BS (Ellis et al., 1998), has been substituted for a more accurate molecular analysis of the BLM gene. However, the analysis of the gene in itself is not enough to understand the effects of genomic instability in the body of patients with the syndrome, making it necessary a more robust and refined analysis of the exome, mapping thousands of genetic variants both rare and common that may be contributing for the phenotype.
Nonetheless, subsequent approaches to elucidating the pathophysiology behind clinical manifestations are capable of interrogating entire sets of transcripts, proteins, and metabolites, in addition to the genome. Evidence-based in clues demonstrate that Bloom’s syndrome can also be influenced by the differentiated expression of genes involved in immune pathways.
Using the RNA-seq methodology for characterization of gene expression in cells via measurement of mRNA levels, Montenegro et al. (2020) detect that genes associated with immune response and apoptosis control presented abnormal expression profile in patients with Bloom’s syndrome. These abnormalities may contribute to the underlying pathophysiology of the disease. However, genes related to DNA repair pathway showed similar expression to controls. This latter finding is contrary to what we originally thought since BS is classically classified as a DNA repair deficiency syndrome.
We still have a long way to go, but the information obtained so far with the use of multiple omics techniques offers a unique opportunity for information underlying the disease, resulting in a way to improve the management, conduct, and treatment of patients. The use of that approach in studies of DNA repair syndromes opens an unprecedented path for understanding important changes observed in so many other diseases, such as cancer, apoptosis, diabetes melito. Who knows what the future holds?
About the author:
Dr. Marilia Moreira Montenegro is a collaborating Professor of the Pathology Department of the Medical School of the University of São Paulo (FMUSP), and Postdoctoral researcher at Citogenomic Laboratory of the Pathology Department of the FMUSP. Her research is focused on translational studies of genomic instability syndromes.
 Montenegro MM, Quaio CR, Palmeira P, et al. Gene expression profile suggesting immunological dysregulation in two Brazilian Bloom’s syndrome cases. Mol Genet Genomic Med. 2020;00:e1133. https ://doi.org/10.1002/mgg3.1133
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 Cunniff, C., Bassetti, J. A., & Ellis, N. A. (2017). Bloom’s Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Mol Syndromol, 8(1), 4-23. doi:10.1159/000452082
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