Cerebellofaciodental Syndrome

A number sign (#) is used with this entry because of evidence that cerebellofaciodental syndrome (CFDS) is caused by homozygous or compound heterozygous mutation in the BRF1 gene (604902) on chromosome 14q32.

Description

Cerebellofaciodental syndrome is an autosomal recessive neurodevelopmental disorder characterized by delayed development, intellectual disability, abnormal facial and dental findings, and cerebellar hypoplasia (summary by Borck et al., 2015).

Clinical Features

Borck et al. (2015) reported 6 children from 3 unrelated families with a neurodevelopmental disorder characterized by microcephaly (-2 to -3 SD), delayed development, and variable intellectual disability with poor speech. Two families were of Italian origin and 1 was Portuguese. All patients had similar craniofacial anomalies, including wave-shaped palpebral fissures, sparse eyebrows, sparse hair, low-set ears, dental malocclusion, and prominent upper incisors. Brain imaging showed cerebellar hypoplasia, thin corpus callosum, and enlarged ventricles. Two sibs also had a hypoplastic pons. Skull and orthopanoramic radiographs showed bialveolar protrusion, prominent alveolar processes, and taurodontism. Other features included scoliosis, short neck and trunk, slender long bones, and tapering fingers. Three patients had laryngeal stridor or laryngomalacia.

Inheritance

The transmission pattern of CFDS in the families reported by Borck et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 3 unrelated families with cerebellofaciodental syndrome, Borck et al. (2015) identified homozygous or compound heterozygous mutations in the BRF1 gene (604902.0001-604902.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder. In vitro functional assays in yeast showed that at least 1 mutation (T259M; 604902.0002) reduced Brf1 occupancy at tRNA target genes, and some mutations (R223W, 604902.0003 and P292H, 604902.0004) impaired cell growth. In yeast, all mutations showed some evidence of impaired RNA polymerase III (Pol III)-dependent transcriptional activity compared to wildtype. The mutations were either completely or partially unable to rescue the neurodevelopmental defects in a zebrafish knockout model. The effects of the variants appeared to be restricted to isoform 2. These findings suggested that BRF1-mediated Pol III transcription, representing basal cellular function, is required for normal cerebellar and cognitive development.

Animal Model

Borck et al. (2015) found that morpholino knockdown of the brf1b gene in zebrafish embryos resulted in microcephaly, significant reduction in size of the optic tectum, and cerebellar hypoplasia. Human BRF1 was able to rescue the phenotype.