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Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome

  • Helgeson, Maria1
  • Keller-Ramey, Jennifer1
  • Knight Johnson, Amy1
  • Lee, Jennifer A.2
  • Magner, Daniel B.3
  • Deml, Brett1
  • Deml, Jacea1
  • Hu, Ying-Ying1
  • Li, Zejuan1
  • Donato, Kirsten1
  • Das, Soma1
  • Laframboise, Rachel4
  • Tremblay, Sandra4
  • Krantz, Ian5
  • Noon, Sarah5
  • Hoganson, George6
  • Burton, Jennifer6
  • Schaaf, Christian P.7, 8
  • del Gaudio, Daniela1
  • 1 University of Chicago, Department of Human Genetics, Chicago, IL, USA , Chicago (United States)
  • 2 Greenwood Genetic Center, Greenwood, SC, USA , Greenwood (United States)
  • 3 IAM Scientific, Inc, Greenville, SC, USA , Greenville (United States)
  • 4 CHU de Quebec, CHUL, Quebec, QC, Canada , Quebec (Canada)
  • 5 The Children’s Hospital of Philadelphia, Division of Human Genetics, Philadelphia, PA, USA , Philadelphia (United States)
  • 6 University of Illinois College of Medicine, Peoria, IL, USA , Peoria (United States)
  • 7 Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA , Houston (United States)
  • 8 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital,, Houston, TX, USA , Houston (United States)
Published Article
Journal of Human Genetics
Springer Nature
Publication Date
Dec 26, 2017
DOI: 10.1038/s10038-017-0387-6
Springer Nature


Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.

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