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

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 intra... Full description

Journal Title: Journal of human genetics 2018, Vol.63 (3), p.349-356
Main Author: Helgeson, Maria
Other Authors: Keller-Ramey, Jennifer , Knight Johnson, Amy , Lee, Jennifer A , Magner, Daniel B , Deml, Brett , Deml, Jacea , Hu, Ying-Ying , Li, Zejuan , Donato, Kirsten , Das, Soma , Laframboise, Rachel , Tremblay, Sandra , Krantz, Ian , Noon, Sarah , Hoganson, George , Burton, Jennifer , Schaaf, Christian P , Del Gaudio, Daniela
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: England: Nature Publishing Group
ID: ISSN: 1434-5161
Link: https://www.ncbi.nlm.nih.gov/pubmed/29279609
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recordid: cdi_proquest_miscellaneous_1981056860
title: Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome
format: Article
creator:
  • Helgeson, Maria
  • Keller-Ramey, Jennifer
  • Knight Johnson, Amy
  • Lee, Jennifer A
  • Magner, Daniel B
  • Deml, Brett
  • Deml, Jacea
  • Hu, Ying-Ying
  • Li, Zejuan
  • Donato, Kirsten
  • Das, Soma
  • Laframboise, Rachel
  • Tremblay, Sandra
  • Krantz, Ian
  • Noon, Sarah
  • Hoganson, George
  • Burton, Jennifer
  • Schaaf, Christian P
  • Del Gaudio, Daniela
subjects:
  • Breakpoints
  • Cohesin
  • Copy number
  • Gene deletion
  • Lymphocytes
  • Mutation
  • Neurodevelopmental disorders
  • X-chromosome inactivation
ispartof: Journal of human genetics, 2018, Vol.63 (3), p.349-356
description: 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.
language: eng
source:
identifier: ISSN: 1434-5161
fulltext: no_fulltext
issn:
  • 1434-5161
  • 1435-232X
url: Link


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titleMolecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome
creatorHelgeson, Maria ; Keller-Ramey, Jennifer ; Knight Johnson, Amy ; Lee, Jennifer A ; Magner, Daniel B ; Deml, Brett ; Deml, Jacea ; Hu, Ying-Ying ; Li, Zejuan ; Donato, Kirsten ; Das, Soma ; Laframboise, Rachel ; Tremblay, Sandra ; Krantz, Ian ; Noon, Sarah ; Hoganson, George ; Burton, Jennifer ; Schaaf, Christian P ; Del Gaudio, Daniela
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descriptionCornelia 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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subjectBreakpoints ; Cohesin ; Copy number ; Gene deletion ; Lymphocytes ; Mutation ; Neurodevelopmental disorders ; X-chromosome inactivation
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descriptionCornelia 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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authorHelgeson, Maria ; Keller-Ramey, Jennifer ; Knight Johnson, Amy ; Lee, Jennifer A ; Magner, Daniel B ; Deml, Brett ; Deml, Jacea ; Hu, Ying-Ying ; Li, Zejuan ; Donato, Kirsten ; Das, Soma ; Laframboise, Rachel ; Tremblay, Sandra ; Krantz, Ian ; Noon, Sarah ; Hoganson, George ; Burton, Jennifer ; Schaaf, Christian P ; Del Gaudio, Daniela
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abstractCornelia 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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