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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 &gt;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.

human molecular genetics

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