MAY 09, 2018 07:30 AM PDT

Keynote Presentation: Informing Clinical Interpretations of Structural Chromosome Rearrangements: Implementing Evolving Knowledge from Chromatin Structure

C.E. CREDITS: CME | CEU | P.A.C.E. CE | Florida CE
  • Professor, Harvard Medical School, Director of Cytogenetics, Brigham and Women's Hospital
      Cynthia Casson Morton received her Bachelor of Science degree from the College of William and Mary in Virginia and her Ph.D. in Human Genetics from the Medical College of Virginia in Richmond. She is the William Lambert Richardson Professor of Obstetrics, Gynecology and Reproductive Biology and Professor of Pathology at Harvard Medical School, Director of Cytogenetics and Past Director of the Biomedical Research Institute at Brigham and Women's Hospital. She is an Institute Member of the Broad Institute of MIT and Harvard. Dr. Morton is an adjunct faculty member of the University of Manchester where she holds a position as Chair in Auditory Genetics. Dr. Morton is certified by the American Board of Medical Genetics in Ph.D. Medical Genetics, Clinical Cytogenetics and Clinical Molecular Genetics. Her research interests are in molecular cytogenetics, hereditary deafness, genetics of uterine leiomyomata and human developmental disorders. She has published over 275 original articles. Dr. Morton is a past member of the Board of Directors of the American Board of Medical Genetics. She was the Chair of the Molecular Genetic Pathology Policy and Exam Committees of the American Board of Medical Genetics and the American Board of Pathology. She served as Member and Chair of the Board of Scientific Counselors of the National Institute of Deafness and Other Communication Disorders, and as Member and Chair of the Board of Regents of the National Library of Medicine. Dr. Morton is currently a member of the Counsel of Scientific Trustees of the Hearing Health Foundation, and Chair of the Veteran's Administration Genomic Medicine Program Advisory Committee. Dr. Morton is a member of the Board of Directors of the American Society of Human Genetics and served as the 2014 President. She recently completed a six year tenure as Editor of The American Journal of Human Genetics and is currently Co-Editor of Human Genetics.


    The arrangement of chromatin inside the nucleus has long been recognized as a key element in genomic stability and an active participant in transcriptional control. With the development and diverse adaptations of the chromosome conformation capture technique (3C), it has become possible to discover many organizational units of the chromatin fiber at the sub-chromosomal and chromosomal scale. Among the most important of these structures are the topologically associating domains (TADs), regions of ~1Mb in size that partition chromosomes into modular structures which are remarkably evolutionarily conserved. Besides their DNA packaging contribution, TADs are recognized as safekeepers of transcriptional control by limiting enhancer-promoter interactions within a defined region, and avoiding awry activation or repression of genes outside the domains.

    In this exciting era of “Next-Gen Cytogenetics”, integration of genomic sequencing into the clinical diagnostic setting can provide precise delineation of chromosomal structural rearrangements at nucleotide level. Given the increased risk for congenital abnormalities with de novo balanced chromosome rearrangements, comprehensive interpretation of breakpoints may substantially improve prediction of phenotypic outcomes. A systematic approach for evaluating sequencing results of chromosome rearrangements can be undertaken in light of regulatory chromatin domains: in addition to genes directly located at the breakpoints, dysregulated protein coding genes and non-coding regions can be assessed in relation to TADs, given their role in pathologic rewiring of the human genome through structural rearrangements. Convergent genomic evidence and predicted probability of exhibiting haploinsufficiency is analyzed through publicly available databases including the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) and Developmental Disorders Genotype-Phenotype Database (DDG2P). Our analyses highlight the important interplay between chromosome organization and disease, and further demonstrate the feasibility of utilizing topological information to predict pathogenic gene-dosage effects. Such analyses can further aid in clinical diagnosis of "n-of-one" samples of non-coding chromosome rearrangements, complementing and enhancing interpretation of current sequencing and array results.

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