PMID- 26382709
OWN - NLM
STAT- MEDLINE
DCOM- 20160921
LR  - 20181113
IS  - 1531-698X (Electronic)
IS  - 1040-8703 (Print)
IS  - 1040-8703 (Linking)
VI  - 27
IP  - 6
DP  - 2015 Dec
TI  - Mutations in the noncoding genome.
PG  - 659-64
LID - 10.1097/MOP.0000000000000283 [doi]
AB  - PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.
FAU - Scacheri, Cheryl A
AU  - Scacheri CA
AD  - 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.
FAU - Scacheri, Peter C
AU  - Scacheri PC
LA  - eng
GR  - R01 CA160356/CA/NCI NIH HHS/United States
GR  - R01CA160356/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
PL  - United States
TA  - Curr Opin Pediatr
JT  - Current opinion in pediatrics
JID - 9000850
RN  - 0 (Chromatin)
SB  - IM
MH  - Chromatin/*genetics/metabolism
MH  - Clustered Regularly Interspaced Short Palindromic Repeats/*genetics
MH  - Gene Expression Profiling
MH  - Genetic Predisposition to Disease/*genetics
MH  - Genome-Wide Association Study
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Mutation/*genetics
MH  - Promoter Regions, Genetic
MH  - Quantitative Trait Loci/*genetics
PMC - PMC5084913
MID - NIHMS730645
COIS- Cheryl Scacheri is a paid employee of GeneDx, a for-profit company that 
      specializes in diagnostic sequencing. The views and opinions expressed in this 
      article are those of the authors and do not necessarily reflect those of GeneDx.
EDAT- 2015/09/19 06:00
MHDA- 2016/09/23 06:00
PMCR- 2016/12/01
CRDT- 2015/09/19 06:00
PHST- 2015/09/19 06:00 [entrez]
PHST- 2015/09/19 06:00 [pubmed]
PHST- 2016/09/23 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - 10.1097/MOP.0000000000000283 [doi]
PST - ppublish
SO  - Curr Opin Pediatr. 2015 Dec;27(6):659-64. doi: 10.1097/MOP.0000000000000283.