title: Mutations in the noncoding genome.
abstract: OBJECTIVE
  Clinical diagnostic sequencing currently focuses on identifying causal mutations in the exome, wherein most disease-causing mutations are known to occur. The rest of the genome is mostly comprised of regulatory elements that control gene expression, but these have remained largely unexplored in clinical diagnostics due to the high cost of whole genome sequencing and interpretive challenges. The purpose of this review is to illustrate examples of diseases caused by mutations in regulatory elements and introduce the diagnostic potential for whole genome sequencing. Different classes of functional elements and chromatin structure are described to provide the clinician with a foundation for understanding the basis of these mutations.
  
  
  RESULTS
  The utilization of whole-genome sequence data, epigenomic maps and induced pluripotent stem (IPS) cell technologies facilitated the discovery that mutations in the pancreas-specific transcription factor 1a enhancer can cause isolated pancreatic agenesis. High resolution array comparative genomic hybridisation (CGH), whole-genome sequencing, maps of 3-D chromatin architecture, and mouse models generated using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas were used to show that disruption of topological-associated domain boundary elements cause limb defects. Structural variants that reposition enhancers in somatic cells have also been described in cancer.
  
  
  CONCLUSIONS
  Although not ready for diagnostics, new technologies, epigenomic maps, and improved knowledge of chromatin architecture will soon enable a better understanding and diagnostic solutions for currently unexplained genetic disorders.
authors.affiliation: aCourtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801 bDepartment of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine; Cleveland, Ohio, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Scacheri
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
mesh_terms: D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D002843:Chromatin