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

Frank J. Kaiser, Morad Ansari, Diana Braunholz, María Concepción Gil-Rodríguez, Christophe Decroos, Jonathan J. Wilde, Christopher T. Fincher, Maninder Kaur, Masashige Bando, David J. Amor, P. S. Atwal, Melanie Bahlo, Christine M. Bowman, Jacquelyn J. Bradley, Han G. Brunner, Dinah Clark, Miguel Del Campo, Nataliya Di Donato, Peter Diakumis, Holly DubbsDavid A. Dyment, Juliane Eckhold, Sarah Ernst, Jose C. Ferreira, Lauren J. Francey, Ulrike Gehlken, Encarna Guillén-Navarro, Yolanda Gyftodimou, Bryan D. Hall, Raoul Hennekam, Louanne Hudgins, Melanie Hullings, Jennifer M. Hunter, Helger Yntema, A. Micheil Innes, Antonie D. Kline, Zita Krumina, Hane Lee, Kathleen Leppig, Sally Ann Lynch, Mark B. Mallozzi, Linda Mannini, Shane Mckee, Sarju G. Mehta, Ieva Micule, Care Rare Canada Consortium, Shehla Mohammed, Ellen Moran, Geert R. Mortier, Joe Ann S. Moser, Sarah E. Noon, Naohito Nozaki, Luis Nunes, John G. Pappas, Lynette S. Penney, Antonio Pérez-Aytés, Michael B. Petersen, Beatriz Puisac, Nicole Revencu, Elizabeth Roeder, Sulagna Saitta, Angela E. Scheuerle, Karen L. Schindeler, Victoria M. Siu, Zornitza Stark, Samuel P. Strom, Heidi Thiese, Inga Vater, Patrick Willems, Kathleen Williamson, Louise C. Wilson, Hakon Hakonarson, Fabiola Quintero-Rivera, Jolanta Wierzba, Antonio Musio, Gabriele Gillessen-Kaesbach, Feliciano J. Ramos, Laird G. Jackson, Katsuhiko Shirahige, Juan Pié, David W. Christianson, Ian D. Krantz, David R. Fitzpatrick, Matthew A. Deardorff*

*Corresponding author for this work
45 Citations (Scopus)


Cornelia de Lange syndrome (CdLS) is amultisystemgenetic 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.Wealso 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.

Original languageEnglish
Article numberddu002
JournalHuman Molecular Genetics
Issue number11
Pages (from-to)2888-2900
Number of pages13
Publication statusPublished - 01.01.2014


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