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

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.

Clinical utility gene card for: Cornelia de Lange syndrome

“…11,12 Mutations in the HDAC8 gene account for~4% of mutations in individuals, including a phenotypically distinct subgroup of CdLS. 13,14 Reported mutations include missense (the most frequent type), chromosomal microdeletions or microduplications, nonsense and splice site.…”

“…14 Although the vast majority of patients with the classic/severe CdLS phenotype carry an identifiable mutation in NIPBL, in some of them no mutation was identified in any of the known CdLS-associated genes. Most of these cases are possibly owing to mosaicism, which in some individuals can be difficult to discern.…”

<b><i>HDAC8</i></b> Loss of Function and <b><i>SHOX</i></b> Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype

“…HDAC8 is a distinct histone deacetylase and mutations in this X-linked gene were found in a variety of patients, ranging from classic cases of Cornelia de Lange syndrome [Deardorff et al, 2012;Kaiser et al, 2014] to mild ID without striking dysmorphism, especially in females [Parenti et al, 2016]. Most female carriers show a completely skewed X inactivation, irrespective of their phenotype.…”

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

“…SMC1A are located in the X chromosome, affected females with heterozygous HDAC8 or SMC1A mutations have been reported [Deardorff et al, 2007;Kaiser et al, 2014]. Most mutations in HDAC8 are missense and de novo.…”

“…In general, males with HDAC8 mutations tend to show more severe manifestations compared to females. Although heterozygous females with HDAC8 mutations can be asymptomatic, affected heterozygous females were also reported, depending on the skewing level of X inactivation [Kaiser et al, 2014]. HDAC8 mutations produce loss of function in the acetyltransferase activity [Deardorff et al, 2012a;Kaiser et al, 2014].…”