María Concepción Gil-Rodríguez, Angela E. Scheuerle, Kathleen A. Leppig, Hane Lee, Miguel Del Campo, Peter Diakumis, Katsuhiko Shirahige, Encarna Guillén-Navarro, Juliane Eckhold, Sally Ann Lynch, Holly Dubbs, A. Micheil Innes, Joe Ann S. Moser, Sulagna C. Saitta, Naohito Nozaki, Fabiola Quintero-Rivera, Helger G. Yntema, Antonie D. Kline, Antonio Perez-Aytes, Dinah Clark, Patrick Willems, Lynette S. Penney, Bryan D. Hall, David A. Dyment, Samuel P. Strom, Matthew A. Deardorff, Maninder Kaur, Kathleen A. Williamson, Diana Braunholz, Ieva Micule, Jennifer M. Hunter, Jose Ferreira, Laird G. Jackson, Sarah Ernst, Paldeep S. Atwal, Raoul C.M. Hennekam, Shane McKee, Sarju G. Mehta, David R. FitzPatrick, Sarah E. Noon, David J. Amor, Yolanda Gyftodimou, David W. Christianson, Louanne Hudgins, Christopher T. Fincher, Melanie Hullings, Inga Vater, Victoria Mok Siu, Feliciano J. Ramos, Michael B. Petersen, Christophe Decroos, Antonio Musio, Morad Ansari, Elizabeth Roeder, Nicole Revencu, Heidi Thiese, Shehla Mohammed, Beatriz Puisac, Louise C. Wilson, John Pappas, Lauren J. Francey, Zita Krumina, Zornitza Stark, Karen L. Schindeler, Juan Pié, Ellen Moran, Jolanta Wierzba, Nataliya Di Donato, Hakon Hakonarson, Frank J. Kaiser, Gabriele Gillessen-Kaesbach, Geert Mortier, Han G. Brunner, Linda Mannini, Melanie Bahlo, Jonathan J. Wilde, Masashige Bando, Jacquelyn J. Bradley, Mark B. Mallozzi, Ulrike Gehlken, Christine M. Bowman, Luis Nunes, Ian D. Krantz, Amsterdam Neuroscience, Amsterdam Public Health, Human Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, CareRare Canada Consortium, and University of Washington Center for Mendelian Genomics
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. © The Author 2014. Published by Oxford University Press. All rights reserved.Published by Oxford University Press. All rights reserved.