Gabriele-De Vries Syndrome

A number sign (#) is used with this entry because of evidence that Gabriele-de Vries syndrome (GADEVS) is caused by heterozygous mutation in the YY1 gene (600013) on chromosome 14q32.

Description

Gabriele-de Vries syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable cognitive impairment, often with behavioral problems, feeding problems, some movement abnormalities, and dysmorphic facial features. Affected individuals may also have a variety of congenital abnormalities (summary by Gabriele et al., 2017).

Clinical Features

Gabriele et al. (2017) reported 10 unrelated patients, ranging in age from 1 to 39 years, with a neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability. Most had mild intrauterine growth retardation. The phenotype was highly variable; some patients started walking around 15 months of age, had mild cognitive impairment, and could attend special schools, whereas at least 1 patient had severe cognitive impairment, was nonverbal, and started walking at age 6.5 years. Most had speech delay, and about half had behavioral problems, such as anxiety and autistic features. Common dysmorphic facial features included facial asymmetry, broad forehead, simple and posteriorly rotated ears, periorbital fullness, downslanting palpebral fissures, strabismus, full nasal tip, malar flattening, indented upper lip, and thick lower lip. Features observed in only a few patients included pointed chin, high palate, ptosis, sparse eyebrows, and micrognathia. Most patients had feeding difficulties and mild distal skeletal abnormalities; some had abnormal movement, such as tremor, dystonia, and waddling gait. Variable additional features were also found in 1 or 2 patients: craniosynostosis, extensible skin, lacrimal duct stenosis, esophageal atresia, hypothyroidism, tooth abnormalities, and cryptorchidism. Five patients had nonspecific abnormal brain imaging showing delayed myelination, frontal gliosis, white matter abnormalities, and/or enlarged ventricles.

Cytogenetics

Gabriele et al. (2017) identified 13 unrelated individuals with de novo heterozygous deletions of chromosome 14q involving the YY1 gene and other genes. The deletions ranged in size from 75 kb to 13 Mb, and over half also overlapped with the UPD(14) gene cluster, resulting in a maternal or paternal UPD(14) phenotype (608149). The phenotype overlapped with that observed in patients with point mutations in the YY1 gene.

Molecular Genetics

In 10 unrelated patients with Gabriele-de Vries syndrome, Gabriele et al. (2017) identified 10 different de novo heterozygous missense or truncating mutations in the YY1 gene (see, e.g., 600013.0001-600013.0005). The missense mutations affected conserved residues in the zinc finger DNA-binding domains. One of the patients had originally been identified by Vissers et al. (2010) in a family-based exome sequencing study of 10 case-parent trios of de novo mental retardation. The mutation in the second patient reported by Gabriele et al. (2017) was found by targeted sequencing of the YY1 gene in 500 individuals with intellectual disability; the remaining mutations were found by exome sequencing of a total cohort of 14,969 individuals with intellectual disability. Chromatin immunoprecipitation studies of lymphoblastoid cells derived from 2 patients with missense mutations and 1 patient with a truncating mutation showed a marked global loss of YY1 DNA binding compared to controls, indicating haploinsufficiency as the pathogenic mechanism, even for missense mutations. Patient samples showed a marked decrease in H3K27 acetylation of YY1-bound active enhancers, as well as an increase in H3K27 methylation, which is associated with repression. Patient cells showed differential expression, usually downregulation, of certain target genes, including those involved in other neurodevelopmental disorders. The findings indicated that the disorder results from dysregulation of key transcriptional regulators.