Non-heritable malformative skeletal diseases caused by somatic mutations (#63)
Elegant clinical and biochemical insights led to the discovery that a somatically arising mutation in GNAS is responsible for causing McCune-Albright syndrome. In contrast, massively parallel sequencing and computational sequence data analyses were needed to identify causal mutations for other non-hereditary malformative diseases affecting the skeleton. I will describe general clinical features of non-heritable diseases caused by somatic mutation and introduce examples of these disorders, including Proteus Syndrome and Klippel-Trenaunay Syndrome. I will detail methods for discovering and for clinically testing responsible genes in affected individuals, and will explain how this new knowledge suggests strategies for treating these disorders. Finally, I will discuss the issue of somatic mutation detection in mice that utilize conditional alleles with either Cre-recombinase or Flp-recombinase, since off-target or unexpected sites of recombination may confound data interpretation. The same technologies that enable sensitive and specific somatic mutation detection in patients with somatic mutations can detect and quantify gene activation/inactivation in mice with conditional alleles.