TY - JOUR
T1 - Molecular characterization of HDAC8 deletions in individuals with atypical Cornelia de Lange syndrome
AU - Helgeson, Maria
AU - Keller-Ramey, Jennifer
AU - Knight Johnson, Amy
AU - Lee, Jennifer A.
AU - Magner, Daniel B.
AU - Deml, Brett
AU - Deml, Jacea
AU - Hu, Ying Ying
AU - Li, Zejuan
AU - Donato, Kirsten
AU - Das, Soma
AU - Laframboise, Rachel
AU - Tremblay, Sandra
AU - Krantz, Ian
AU - Noon, Sarah
AU - Hoganson, George
AU - Burton, Jennifer
AU - Schaaf, Christian P.
AU - Del Gaudio, Daniela
N1 - Publisher Copyright:
© 2017 The Japan Society of Human Genetics.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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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U2 - 10.1038/s10038-017-0387-6
DO - 10.1038/s10038-017-0387-6
M3 - Article
C2 - 29279609
AN - SCOPUS:85039052870
SN - 1434-5161
VL - 63
SP - 349
EP - 356
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 3
ER -