A new inherited DNA repair deficiency syndrome, which increases a patient’s risk of developing blood cancer but also leaves them susceptible to DNA damage from chemotherapy, has been identified by a UK research team, highlighting the need to tailor cancer treatment regimens to minimise toxicity in affected patients.
Writing in the journal Nature Communications, the research team, led by the University of Birmingham, reported the discovery of DIAPH1 Loss-of-function (DIAL) syndrome, which is characterised by biallelic loss-of-function mutations in the actin nucleating factor diaphanous-related formin 1 (DIAPH1 or mDia1) and causes clinical symptoms early in life.
The DIAPH1 gene mutations were identified in a single index patient, who had symptoms including microcephaly, behavioural abnormalities, intellectual disabilities, cortical blindness and seizures.
Working with neurogeneticists at University College London, researchers later identified more than 30 patients with these mutations, all of whom exhibited similar symptoms such as microcephaly, intellectual disability, impaired vision and seizures.
Among the cohort, one patient developed Hodgkin lymphoma, and another developed a large B cell lymphoma.
In addition, the clinical symptoms in this cohort were strikingly similar to the DNA repair disorders Nijmegen breakage syndrome (NBS) and Warsaw breakage syndrome, both of which are risk factors of blood cancer.
This finding prompted the team to investigate whether DIAPH1 functioned to regulate the actin-dependent DNA double strand break repair (DSBR) process, which was fundamental to maintain genome stability and prevent the onset of disease.
Through a series of cell analyses, they showed DIAPH1 was essential for facilitating homologous recombination (HR)-dependent repair of DNA double strand breaks induced by ionising radiation and the chemotherapeutic agents, camptothecin and etoposide.
‘Taken together, we identify DIAL syndrome as a previously undiscovered DSBR deficiency syndrome associated with neurodevelopmental abnormalities and tumour predisposition akin to those observed in patients with NBS,’ the study authors concluded.
‘Furthermore, we demonstrate that loss of DIAPH1 results in defective HR-dependent DNA repair, which is consistent with many of the clinical deficits exhibited by affected patients as well as the suggestion that in some cases DIAPH1 may act as a tumour suppressor.’
DNA repair deficiency syndromes and anti-cancer treatment
Study corresponding author Professor Grant Stewart, professor of cancer genetics in the Department of Cancer and Genomic Sciences at the University of Birmingham, said patients with inherited DNA repair deficiency syndromes were ‘usually 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,’ he said.
‘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.’
Professor Stewart said the research was crucial for affected patients and their families, as it not only provided a diagnosis for a previously unrecognised genetic condition but also informed parents and medical professionals about disease progression, potential complications, and cancer risks.
He added: ‘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.’
The researchers want to ensure DIAL syndrome is included in sequencing panels to allow newborn diagnosis and give the opportunity for more personalised therapeutic regimes to be used if individuals with DIAL syndrome develop cancer.
Dr Laura Danielson, children’s and young people’s research lead at Cancer Research UK – the charity that funded the research – welcomed the study’s findings and the potential for more personalised care.
‘It’s a powerful example of how research can make a real difference, even in the rarest of cases,’ she said.
