Certain kinds of mutations, especially those present in only a small fraction of the body’s cells, also referred to as somatic mutations, may not be discovered by current methods.
"Our research findings have implications on understanding genetic diseases in general, especially for similar disorders like autism and schizophrenia. The research findings will not only offer patients and their families gene-specific prognosis, but provide accurate assessment of recurrence risk for future pregnancies."
Dr Saumya Shekhar Jamuar, Consultant, Genetics Service, Department of Paediatrics, KKH
For patients with diseases or conditions caused by gene mutations, genetic diagnosis is essential. It allows us to provide gene-specific management, offer potential targeted therapies and can be used to counsel such patients and their families in future pregnancies. However, certain kinds of mutations, especially those present in only a small fraction of the body’s cells, also referred to as somatic mutations, may not be discovered by current methods.
Said KKH’s Dr Saumya Shekhar Jamuar, Consultant, Genetics Service, Department of Paediatrics, “The current gold standard of diagnostic gene testing uses a traditional DNA sequencing technique known as the Sanger method. However, with this method, we miss a significant proportion of somatic mutations because we are using a test that’s not designed to look for them.”
Dr Jamuar led a team of researchers who came up with the new technique. The researchers used a “deep sequencing” technique to identify hard-to-find diseasecausing gene mutations by focusing on a small subset of genes and sequencing them to greater depths than routinely performed. In their study, these somatic mutations were found in more than a quarter of the patients with identified mutations. If traditional sequencing methods had been used, five of the eight somatic mutations that the team identified would never have been found.
“We were seeing patients in the clinic who appeared to have a particular disorder, but the cause could not be identified despite genetic testing. The idea of somatic mutations as a cause of their disorder had been suggested by our group previously, but it had never been systematically studied. So we embarked on our research study to test the sensitivity and diagnostic yield of our deep sequencing method.”
Dr Jamuar, who was a clinical fellow at Boston Children’s Hospital, led the study in gene testing, under the supervision of Dr Christopher A. Walsh, investigator at Howard Hughes Medical Institute and Chief of the Division of Genetics and Genomics at Boston Children’s Hospital.
“I designed and performed the experiments in the study. This involved setting up a test to screen blood samples from 158 patients whose brain malformations remained unexplained. My part included designing the gene-sequencing panel, performing the deep sequencing experiments, analysing the results and performing validation experiments,” Dr Jamuar explained. “As I had to return to Singapore, other team members carried out additional experiments and I worked remotely to help the team complete the study.”
Given the sensitivity shown by the new method in detecting somatic mutations, Dr Jamuar is confident that it would be a useful tool for medical geneticists before they need to consider other more costly sequencing methods. While no test offers a single solution for all patients, their complementary strengths give geneticists a more complete set of tools.
“Our research findings have implications on understanding genetic diseases in general, especially for similar disorders like autism and schizophrenia. The research findings will not only offer patients and their families gene-specific prognosis, but provide accurate assessment of recurrence risk for future pregnancies.”
According to Dr Jamuar, KKH is in the process of acquiring the equipment necessary for the new method and has plans to offer this technique of gene testing to patients in the near future. The finding was reported in the August 21, 2014, issue of the New England Journal of Medicine.
This article was published in Tomorrow's Medicine Issue 15.
