I will describe non-cancerous skeletal diseases that occur as a consequence of somatic mutation. I will introduce the work of Drs Mary Lyon, Dorothea Bennett, and Rudolf Happle that provided insights into the mechanism responsible for several genetic, non-heritable diseases. I will then describe the technology and analytic strategies that several laboratories, including my own, employed to identify mutations in patients with Maffucci, Proteus, CLOVES, and Klippel-Trenaunay syndromes, Ollier disease, and macrodactyly. Many presumed somatic mosaic skeletal conditions, such as Gorham-Stout disease, remain unsolved and I will mention the obstacles that have, thus far, kept labs from discovering their causes.
The remainder of my talk will be focused on somatic PIK3CA mutations, which unexpectedly to me at least are associated with a wide spectrum of clinical phenotypes. I will detail how we have been using droplet digital PCR (ddPCR) and single molecule molecular inversion probes (smMIPs) to search for low abundance mutations in patients. I will also describe approaches that employ model organisms to determine whether a somatic mutation is necessary and sufficient to cause disease and, if so, which component features of the disease can be prevented, delayed, or reversed. I will conclude by addressing treatment strategies for patients with malformations caused by PIK3CA somatic mutation.
Disclosure: The author declared no competing interests.
Biographical details: Dr M L Warman is the Harriet M Peabody Professor of Orthopaedic Surgery and Genetics at Harvard Medical School. He attended college at Brown University and Medical School at Cornell University. While in medical school, he performed research with Dr Adele Boskey at The Hospital for Special Surgery. After medical school he trained in Pediatrics at the Childrens Hospital in Washington, DC, in Genetics at the Childrens Hospital in Boston, and he performed post-doctoral research with Professor Bjorn R Olsen at Harvard Medical School. In 1994, Dr M L Warman established an independent laboratory and clinical program in the Department of Genetics and Center for Human Genetics at Case Western Reserve University and University Hospitals of Cleveland. In 2006, he returned to Boston to become director of the Orthopaedic Research Laboratories at Boston Childrens Hospital. Dr M L Warman is also an investigator with the Howard Hughes Medical Institute. The patients and families, who Dr. M L Warman has come to know through his clinical work as a pediatrician and geneticist, have often served as the impetus for his research. In addition to working with patients and families, members of Dr M L Warmans lab try to understand and treat human disease by studying cultured cells, purified proteins, and other organisms. Having benefited from superb mentoring throughout his career, Dr M L Warman enjoys introducing students (from high school to professional school) to the importance and excitement of Human Genetics. He is proud to have mentored students at all levels, who have gone on to become excellent scientists, physicians, and educators.
27 - 30 Jun 2015