The lack of DIAPH1 impairs the body’s ability to properly regulate B cell development and function, and means that patients are more likely to develop B-cell Lymphoma. As radiotherapy and chemotherapy work by damaging DNA in both healthy and cancerous cells, the lack of DIAPH1 also results in affected patients with the syndrome being unable to repair the damage caused by these treatments. Unrepaired DNA damage in normal cells of the body can cause these cells to die, which can lead to life-threatening side effects.
Professor Grant Stewart from the University of Birmingham and corresponding author of the study said:
“Patients with inherited DNA repair deficiency syndromes usually are children who are very sick. In addition to developmental abnormalities that affect many different organs, these patients are often prone to developing cancer. Unfortunately, the DNA repair defect that is present in every cell in their body makes them extremely sensitive to the therapy that would normally be used to treat their cancer.”
“While inherited DNA repair deficiency syndromes like DIAL syndrome are rare, it is critical to identify children with these conditions early in life - especially before starting anti-cancer treatment to avoid life-threatening consequences.
“This research is crucial for affected patients and their families, as it not only provides a diagnosis for a previously unrecognised genetic condition but also informs parents and medical professionals about disease progression, potential complications, and cancer risks. Additionally, this research will help guide oncologists in adjusting cancer treatment protocols to minimise toxicity in affected patients, potentially improving both their quality of life and treatment outcomes.”
19 years with one patient
One patient who has been working with geneticists for more than 19 years was instrumental in discovering DIAL syndrome.
The research team at the University of Birmingham provides pro-bono support for individuals through functional genetic diagnostics especially for patients with unknown genetic disorders associated with increased chromosome breakage. A patient with symptoms similar to other known DNA repair deficiency disorders was initially referred to the research team in 2006.
However, it wasn’t until recently that the patient was identified as having mutations in the DIAPH1 gene. Through a collaboration with Professor Henry Houlden at University College London a further 32 patients with mutations in the DIAPH1 gene were identified, which indicated that this was a new human syndrome.
Studying cells from these patients lead to the discovery that the DIAPH1 protein works to help cells repair damaged DNA. This enabled the team to identify why children with DIAL syndrome display clinical symptoms similar to known DNA repair deficiency disorders.
Professor Henry Houlden (UCL Queen Square Institute of Neurology) said:
“We in the neurogenetics team have identified that a large number of patients have mutations in the DIAPH1 gene and working with the Birmingham team has allowed us to work on the functional aspects of this. Further clinical and functional work will be essential in identifying more patients and families, biomarkers and treatments.”
The researchers are now working to ensure that DIAL syndrome is included in sequencing panels so that newborn children can be diagnosed, and more personalised therapeutic regimes can be used if patients with DIAL syndrome develop cancer.
Dr Laura Danielson, children’s and young people’s research lead at Cancer Research UK, said:
“DIAL syndrome is extremely rare, but for the families affected, these findings are significant. Research like this will help to ensure that children with inherited genetic syndromes have the possibility to receive more personalised care in the event that they do develop cancer. It’s a powerful example of how research can make a real difference, even in the rarest of cases.”
"However, it's important to remember that for the vast majority of people with cancer, chemotherapy is one of the most effective available treatments. It is vital that patients continue treatments recommended by their doctor."
