期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 11, 页码 2888-2900出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu002
关键词
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资金
- National Institutes of Health [NICHD K08HD055488, GM49758, NICHD P01 HD052860]
- USA CdLS Foundation
- Doris Duke Charitable Foundation
- Children's Hospital of Philadelphia
- Roy & Diana Vagelos Scholars Program in Molecular Life Sciences at the University of Pennsylvania
- University of Lubeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung)
- German Federal Ministry of Education and Research (B.M.B.F.) under the frame of E-Rare-2 (TARGET-CdLS to F.J.K.)
- ERA-Net for Research on Rare Diseases, Research Program of Innovative Cell Biology by Innovative Technology
- Region of Tuscany
- UK Medical Research Council
- Spanish Ministry of Health Fondo de Investigacion Sanitaria (FIS) [PI12/01318]
- Diputacion General de Aragon (Grupo Consolidado B20)
- CIBERER (GCV-HCULB Zaragoza)
- European Social Fund
- Australian Research Council
- National Health and Medical Research Council
- ictorian Government's Operational Infrastructure Support Program
- Australian Government National Health and Medical Research Council IRIISS
- National Human Genome Research Institute
- National Heart, Lung and Blood Institute grant [1U54HG006493]
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute [OGI-049]
- Ontario Research Fund
- Genome Quebec
- Genome British Columbia
- CHEO Foundation
- MRC [MC_U127561093, MC_PC_U127561093] Funding Source: UKRI
- Medical Research Council [MC_U127561093, MC_PC_U127561093] Funding Source: researchfish
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 similar to 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.
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