Understanding phenotypic variability in genomic disorders

Hosted by the Biochemistry and Molecular Biology department. Abstract Recent studies have suggested that many complex genetic disorders are significantly influenced by rare mutations. One type of rare mutation, copy number variants (CNVs), account for approximately 15-20% of the genetic basis of human neurodevelopmental disease, also termed genomic disorders. Classically, CNVs associated with canonical syndromes such as Smith-Magenis syndrome and Williams syndrome arise de novo, are fully penetrant, and manifest with recognizable clinical features with little or no phenotypic variability. However, a majority of recently discovered CNVs are often inherited, with variable penetrance and expressivity, and are found in individuals with a wide range of neurodevelopmental phenotypes including autism, epilepsy, schizophrenia, intellectual disability, and congenital malformations. While these recently identified CNVs confer higher risk for disease, they are not necessarily sufficient genetic factors for disease causation. It is therefore clear that additional genetic factors potentially interacting in a disease-associated pathway be considered to explain phenotypic variability or comorbidity. Such a model has been already shown to be implicated in the pathogenicity of severe developmental delay. Integration of high-throughput exome and whole-genome sequencing data with CNV data on many individuals for a disease in question is the emerging new model to study complex genetic disease.

Contact

  Traci Shimmel
  tks1@psu.edu
  814-867-4373