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

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,