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Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Authors :
Kaiser FJ
Ansari M
Braunholz D
Concepción Gil-Rodríguez M
Decroos C
Wilde JJ
Fincher CT
Kaur M
Bando M
Amor DJ
Atwal PS
Bahlo M
Bowman CM
Bradley JJ
Brunner HG
Clark D
Del Campo M
Di Donato N
Diakumis P
Dubbs H
Dyment DA
Eckhold J
Ernst S
Ferreira JC
Francey LJ
Gehlken U
Guillén-Navarro E
Gyftodimou Y
Hall BD
Hennekam R
Hudgins L
Hullings M
Hunter JM
Yntema H
Innes AM
Kline AD
Krumina Z
Lee H
Leppig K
Lynch SA
Mallozzi MB
Mannini L
McKee S
Mehta SG
Micule I
Mohammed S
Moran E
Mortier GR
Moser JA
Noon SE
Nozaki N
Nunes L
Pappas JG
Penney LS
Pérez-Aytés A
Petersen MB
Puisac B
Revencu N
Roeder E
Saitta S
Scheuerle AE
Schindeler KL
Siu VM
Stark Z
Strom SP
Thiese H
Vater I
Willems P
Williamson K
Wilson LC
Hakonarson H
Quintero-Rivera F
Wierzba J
Musio A
Gillessen-Kaesbach G
Ramos FJ
Jackson LG
Shirahige K
Pié J
Christianson DW
Krantz ID
Fitzpatrick DR
Deardorff MA
Source :
Human molecular genetics [Hum Mol Genet] 2014 Jun 01; Vol. 23 (11), pp. 2888-900. Date of Electronic Publication: 2014 Jan 08.
Publication Year :
2014

Abstract

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Details

Language :
English
ISSN :
1460-2083
Volume :
23
Issue :
11
Database :
MEDLINE
Journal :
Human molecular genetics
Publication Type :
Academic Journal
Accession number :
24403048
Full Text :
https://doi.org/10.1093/hmg/ddu002