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

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

Authors: Kaiser, FJ  Ansari, M  Braunholz, D  Concepcion Gil-Rodriguez, M  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  Guillen-Navarro, E  Gyftodimou, Y  Hall, BD  Hennekam, R  Hudgins, L  Hullings, M  Hunter, JM  Yntema, H  Innes, AM  Kline, AD  Krumina, Z  Lee, H  Leppig, K  Lynch, SA  Mallozzi, MB  Mannini, L  McKee, S  Mehta, SG  Micule, I  Mohammed, S  Moran, E  Mortier, GR  Moser, JA  Noon, SE  Nozaki, N  Nunes, L  Pappas, JG  Penney, LS  Perez-Aytes, 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  Pie, J  Christianson, DW  Krantz, ID  FitzPatrick, DR  Deardorff, MA  Fitzpatrick, David R  Deardorff, MA 
Citation: Kaiser FJ, etal., Hum Mol Genet. 2014 Jun 1;23(11):2888-900. doi: 10.1093/hmg/ddu002. Epub 2014 Jan 8.
RGD ID: 11068490
Pubmed: PMID:24403048   (View Abstract at PubMed)
PMCID: PMC4014191   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddu002   (Journal Full-text)

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 approximately 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cornelia de Lange syndrome 5  IAGP 11068490DNA:missense mutations more ...RGD 
Cornelia de Lange syndrome 5  ISOHDAC8 (Homo sapiens)11068490; 11068490DNA:missense mutations more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac8  (histone deacetylase 8)

Genes (Mus musculus)
Hdac8  (histone deacetylase 8)

Genes (Homo sapiens)
HDAC8  (histone deacetylase 8)


Additional Information