Cornelia De Lange Syndrome 5

A number sign (#) is used with this entry because Cornelia de Lange syndrome-5 (CDLS5) is caused by mutation in the HDAC8 gene (300269) on chromosome Xq13.

Description

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.

Clinical Features

Kaiser et al. (2014) reported the clinical features of 35 individuals with CDLS5. Many features were similar to those observed in typical CDLS, including postnatal growth retardation (28%), microcephaly (29%), hearing loss (59%), gastroesophageal reflux (67%), feeding difficulties (86%), cardiac defects (36%), genitourinary anomalies (44%), and intellectual disabilities (100%). Craniofacial features were also common, such as brachycephaly (70%), arched eyebrows (88%), synophrys (90%), long eyelashes (45%), depressed nasal bridge (45%), anteverted nares (76%), long philtrum (57%), downturned corners of the mouth (57%), small widely spaced teeth (61%), micrognathia (59%), and cleft palate without cleft lip (18%). Most patients also had small hands and feet. Unique features not seen in typical CDLS included delayed fontanel closure (50%), ocular hypertelorism (47%) and/or telecanthus (64%), hooding of the upper eyelids (46%), bulbous nasal tip (66%), dental anomalies (50%), and nevus flammeus (58%). Female mutation carriers were unaffected or less severely affected than males, and most showed signs of skewed X-inactivation.

In a review of the clinical features of 46 reported patients with CDLS5, including the 35 patients reported by Kaiser et al. (2014), Mordaunt and McLauchlan (2015) noted that there is a wide range of severity. Intellectual impairment ranged from mild to severe. No limb deficiency was described in any of the patients, although small hands and feet and minor digit and metacarpal anomalies were frequent. Growth appeared to be less affected in CLDS5 compared to other forms of the disorder.

In a review of CDLS, Boyle et al. (2015) noted that patients with CDLS5 have features similar to those in patients with other forms of the disorder, but they tend to have delayed closing of the anterior fontanel, hypertelorism with hooding of the eyelids, broad nose, well-formed philtrum and upper lip, and dental anomalies. Both affected and unaffected female mutation carriers have been reported.

Clinical Variability

Harakalova et al. (2012) reported a 5-generation Dutch family in which 7 males had a syndromic form of severe intellectual disability and 7 females had a milder phenotype. The males had mental retardation, truncal obesity, gynecomastia, hypogonadism, short stature, small hands, and a typical face characterized by a small head, small ears, prominent supraorbital ridges, deep-set eyes, high malar bones, broad nasal tip, columella somewhat below the nasal alae, thin upper vermilion, and retrognathia. None of the men could live independently. Female carriers had learning disorders and recognizable facial features, including high malar bones and broad nasal tip. In addition, 2 males and 1 female had learning problems without additional features. By next-generation sequencing of the chromosome X exome in this family, Harakalova et al. (2012) identified a mutation in the HDAC8 gene (300269.0001). Female carriers showed complex X inactivation, with preferential silencing of the mutant allele.

Inheritance

The transmission pattern of the mental retardation syndrome reported by Harakalova et al. (2012) was consistent with X-linked dominant inheritance.

Mapping

By linkage analysis of a large Dutch family with syndromic X-linked mental retardation, Harakalova et al. (2012) found linkage to chromosome Xq (maximum lod score of 4.93 at marker DXS983). The candidate region was fine mapped to chromosome Xq11-q22 between DXS983 and DXS986.

Molecular Genetics

In affected members of a large family with a syndromic mental retardation disorder resembling Cornelia de Lange syndrome, Harakalova et al. (2012) identified a splice site mutation in the HDAC8 gene (300269.0001).

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 (300269.0002-300269.0006). 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.

In an international cohort of 586 individuals with features of CDLS and overlapping phenotypes, Kaiser et al. (2014) found that 25 (4%) probands had mutations in the HDAC8 gene. In addition, 7 individuals in whom the diagnosis of CDLS was not considered were found to have HDAC8 mutations by exome sequencing. Twenty-three mutations occurred de novo, 4 families showed maternal inheritance of the mutations, and the inheritance pattern could not be ascertained in 7 families. There was a range of mutation types, and functional studies indicated a variable loss of deacetylase activity, ranging from complete loss to retention of over 50% residual activity.