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

TitleLoss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.
Publication TypeJournal Article
Year of Publication2014
AuthorsKaiser, FJ, Ansari, M, Braunholz, D, Gil-Rodríguez, MConcepció, 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, A Innes, M, Kline, AD, Krumina, Z, Lee, H, Leppig, K, Lynch, SAnn, Mallozzi, MB, Mannini, L, McKee, S, Mehta, SG, Micule, I, Mohammed, S, Moran, E, Mortier, GR, Moser, J-AS, 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
Corporate AuthorsCare4Rare Canada Consortium, University of Washington Center for Mendelian Genomics
JournalHum Mol Genet
Date Published2014 Jun 01
KeywordsAmino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment

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.

Alternate JournalHum. Mol. Genet.
PubMed ID24403048
PubMed Central IDPMC4014191
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
K08HD055488 / HD / NICHD NIH HHS / United States
MC_PC_U127561093 / / Medical Research Council / United Kingdom
GM49758 / GM / NIGMS NIH HHS / United States
MC_U127561093 / / Medical Research Council / United Kingdom
K08 HD055488 / HD / NICHD NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
UM1 HG006493 / HG / NHGRI NIH HHS / United States
1U54HG006493 / HG / NHGRI NIH HHS / United States
P01 HD052860 / HD / NICHD NIH HHS / United States