Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 60% of patients have mutations ... Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 60% of patients have mutations in the NIPBL gene (608667) on chromosome 5p13 (CDLS1; 122470), and about 4 to 6% of patients have mutations in the X-linked SMC1A gene (300040) (CDLS2; 300590) (summary by Musio et al., 2006, Hoppman-Chaney et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see 122470.
Deardorff et al. (2012) screened 154 individuals with Cornelia de Lange syndrome for mutations in the HDAC8 gene. HDAC8 encodes the vertebrate SMC3 (606062) deacetylase. These individuals were negative for mutations in NIPBL, SMC1A, and SMC3, as well ... Deardorff et al. (2012) screened 154 individuals with Cornelia de Lange syndrome for mutations in the HDAC8 gene. HDAC8 encodes the vertebrate SMC3 (606062) deacetylase. These individuals were negative for mutations in NIPBL, SMC1A, and SMC3, as well as RAD21 (606462), STAG2 (300826), ESCO1 (609674), ESCO2 (609353), and MAU2 (614560). They identified 4 de novo missense mutations and 1 de novo nonsense mutation in HDAC8. In addition, one familial mutation was identified in a boy, his mildly affected sister, and his unaffected mother, in which the mutant allele was inactivated in her blood. This mutation was also one of the de novo mutations in an unrelated girl. None of the mutations was seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project. Despite the small numbers and the varied clinical features in females due to random X-chromosome inactivation, the 5 patients reported by Deardorff et al. (2012) demonstrated growth, cognitive, and facial features consistent with those caused by mutations in NIPBL (classic Cornelia de Lange syndrome). Both expression studies and X-chromosome inactivation studies demonstrated complete skewing towards the normal allele in the blood of females with HDAC8 mutations, indicating strong selection against the mutation. Immunoblotting demonstrated minimal HDAC8 protein expression in lymphoblastoid cell lines from a hemizygous boy with a missense mutation, as well as the skin fibroblasts from a female lyonized to express the mutant allele, indicating protein instability in each case. Consistent with this, assessment of acetylated SMC3 demonstrated increased levels in both cell lines.