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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.
- Source :
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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
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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.
- Subjects :
- Amino Acid Sequence
Child
Child, Preschool
Cohort Studies
Cranial Fontanelles enzymology
De Lange Syndrome genetics
Eye Abnormalities genetics
Female
Histone Deacetylases chemistry
Histone Deacetylases metabolism
Humans
Hypertelorism genetics
Infant
Male
Molecular Sequence Data
Mutation, Missense
Phenotype
Repressor Proteins chemistry
Repressor Proteins metabolism
Sequence Alignment
Cranial Fontanelles abnormalities
De Lange Syndrome enzymology
Eye Abnormalities enzymology
Genes, X-Linked
Histone Deacetylases genetics
Hypertelorism enzymology
Repressor Proteins genetics
Subjects
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