Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.
Nijmegen Breakage Syndrome (NBS) is a rare inherited condition that affects both a child’s development and the immune system. People with NBS often have a smaller head size (microcephaly), unique facial features, slower growth pace, and a higher chance of developing certain cancers, especially those affecting the lymphatic system. The main issue in NBS is a problem with repairing damaged DNA due to mutations in the NBN gene, which produces a protein called nibrin. In this article, we will explore the genetic causes of NBS, the role of nibrin in DNA repair, and what these genetic changes mean for people with the condition.
Nijmegen Breakage Syndrome was first described in 1981 in patients from the Nijmegen region of the Netherlands, wherein patients exhibited a group of characteristics including chromosomal instability and heightened cancer risk. As a member of the DNA repair disorders, NBS shares similarities with Ataxia-Telangiectasia and Bloom Syndrome, highlighting the critical role of genome maintenance in human health.
You may also be interested: Understanding the Genetics of Bloom Syndrome
Nibrin is encoded by the NBN gene, located on chromosome 8q21, which comprises 16 exons encoding the 754-amino acid protein nibrin. It is an important protein that helps repair breaks in DNA. It is part of a group of proteins called the MRN complex, which includes three main proteins: MRE11, RAD50, and NBN (nibrin). This complex has two main jobs: finding broken spots in DNA and then starting the repair process. Together, these proteins act like a repair crew, ensuring that damaged DNA gets fixed to keep the cell healthy.Â
Exposure to radiation (like UV or X-rays), chemicals (such as those in tobacco smoke or pollution), and natural cellular processes like DNA replication, and metabolism can cause damage to the DNA, leading to breaks. If not properly repaired, these breaks may result in cell dysfunction or increase risk for diseases like cancer. A 2021 study covering 241 NBS patients with NBN mutations from 11 countries, found a 77.8% cancer incidence at 20 years, with a 20-year survival rate of 44.6%.
The most common mutation in NBS patients is a 5-base pair deletion (657_661del5), leading to a truncated, non-functional protein. This mutation disrupts the MRN complex, impairing DNA repair and resulting in chromosomal instability.
A 2016 study examined whether specific genetic variations in the NBN gene, which plays a role in DNA repair, are linked to an increased risk of breast cancer. Researchers analyzed three NBN gene variants (924 T>C, 8360 G>C, and 30537 G>C) in DNA from women with breast cancer and healthy controls. They found that the NBN gene 924 T>C variant was significantly associated with breast cancer, suggesting it may be a risk factor, while the other two variants showed no significant link to breast cancer..
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A 2019 study highlighted that four genetic variations in the NBN gene lead to alterations in the gene’s coding regions. The SNP rs769420 is linked to conditions like aplastic anemia and the Nijmegen breakage syndrome. Additionally, SNPs rs61753020 and rs12721593 are associated with conditions like microcephaly (with normal intelligence), immune deficiencies, and an increased risk of hereditary cancers.
Defective nibrin leads to:
Patients with NBS typically present with:
Diagnosis involves:
As an autosomal recessive disorder, parents of an affected child are carriers of one mutated allele each. Genetic counseling provides:
Currently, no cure exists for NBS. Management focuses on:
Prophylactic antibiotics and immunoglobulin therapy. A study published in June this year (2024) highlighted that immunoglobulin replacement therapy, given to 58.7% of the study patients, helped reduce severe infections. Improved diagnostic and treatment strategies could enhance patient outcomes.
This treatment is considered in severe immunodeficiency or in hematologic malignancies. A 2021 study involving 241 NBS patients from 11 countries showed that hematopoietic stem cell transplantation (HSCT) improved survival in NBS patients, particularly those who received HSCT before developing cancer, with a markedly lower cancer rate than non-transplanted patients.
Other common treatment options include cancer surveillance for early detection of malignancies and minimizing exposure to diagnostic X-rays and radiotherapy.
Nijmegen Breakage Syndrome underscores the vital importance of intact DNA repair mechanisms in human health. Understanding the genetic basis of NBS has not only improved diagnostic and management strategies for affected individuals but also provided valuable insights into cancer biology and the cellular response to DNA damage. Ongoing research holds promise for more effective therapies that aid in improving the quality of life of patients with NBS.
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