​Genetic diagnosis is essential in counselling patients and their parents by identifying mutations that can be risks to future children. However, certain kinds of mutations may not be discovered by current methods.

Led by Dr Christopher A Walsh, Chief of the Division of Genetics and Genomics at Boston Children’s Hospital, Dr Saumya Jamuar, Consultant at KK Women's and Children's Hospital who was a clinical fellow at Boston Children’s Hospital, and his colleagues at Howard Hughes Medical Institute (HHMI) have devised a way to find hard-to-find mutations not detectable by the current methods.

Most diagnostic gene testing is done by sequencing specific genes using a traditional DNA sequencing technique known as the Sanger method.   “The gold standard of clinical diagnosis is Sanger sequencing,” said Dr Jamuar.  “But you're missing a big chunk of patients with mutations in these genes, because you are using a test that's not designed to look for them.”

The team identified somatic mutations—gene mutations present in some, but not all, cells – in more than a quarter of patients that could be successfully diagnosed genetically.

Five of the eight somatic mutations that they identified would never have been found with traditional sequencing methods.   “All of the mutations that were present at less than about 15 percent of the reads were completely undetectable by Sanger sequencing,” Dr Walsh said.

With the new method's proven sensitivity in detecting somatic mutations, medical geneticists can consider using the approach before turning to more costly sequencing methods.   There is no single solution for all patients, but their complementary strengths give geneticists a more complete set of tools. “Look deep, and you may find the answer,” said Dr Jamuar.

The finding was reported in the 21 August 2014 issue of the New England Journal of Medicine.

Read more at the HHMI website: http://www.hhmi.org/news/gene-technique-identifies-hidden-causes-brain-malformation