Two-time NARSAD Grantee (1998 and 2008) Christopher Walsh, M.D., Ph.D., Chief of the Division of Genetics at Boston Children’s Hospital, and colleagues, have developed a new technique to find disease-causing genetic mutations that are found in only a small fraction of the human body’s cells. These mutations are known as somatic mutations; they are not inherited from parents but instead occur after fertilization. Dr. Walsh’s laboratory seeks to identify the genetic mutations that cause brain malformations associated with intellectual disability, autism spectrum disorder and epilepsy. Since there remain many unanswered questions from research conducted using current genetic sequencing techniques, he and his team set out to develop a method that could effectively identify these harder-to-find somatic mutations.

The researchers targeted genes known or suspected to be associated with brain malformations and then sought to sequence them “a thousand times over,” Dr. Walsh explains in Howard Hughes Medical Institute (HHMI) News (Dr. Walsh is an HHMI Investigator). Typical genetic sequencing uses a technique known as the Sanger method that homes in on specific genes, and then if that strategy fails to identify a mutation, researchers sometimes broaden the search to include all of the protein-coding regions of the genome (called the exome), or even further, to the entire genome. Those techniques are not designed to find mutations that occur only in a small fraction of cells, Dr. Walsh says. “Even if you are looking at the right gene, you can still miss the mutation.”

Dr. Walsh and team worked with the DNA of 158 patients with a variety of brain disorders and brain malformations that remained unexplained, despite prior genetic sequencing. For their analysis, a panel of 14 or 54 genes (depending on the patient's condition) was sequenced hundreds or thousands of times. Following this, existing algorithms were fine-tuned and used to search for somatic mutations in the sequences; this labor-intensive work required some additional months of work.  

The results of their research, published August 21st  in The New England Journal of Medicine, report that for more than a quarter of the patients (27 of the 158), the team successfully identified mutations likely to cause disease. Eight of these were somatic mutations, present in just five to 35 percent of the sequenced DNA. Dr. Walsh told HHMI News that his team was surprised to discover so many somatic mutations in patients who had already undergone genetic testing. “This tells us just how poorly other methods perform in detecting somatic mutations. You're not going to find these things unless you go looking for them—unless you have a clinical test that is set up to detect them in a sensitive way."

“We think these somatic mutations are probably more common as causes of intellectual disability, and maybe even some psychiatric conditions, than people have generally realized,” Dr. Walsh says. “It's really time to start investigating that systematically.”

Read the paper abstract.

Read the article in HHMI News.