Neurodevelopmental Disorder With Structural Brain Anomalies And Dysmorphic Facies

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with structural brain anomalies and dysmorphic facies (NEDBAF) is caused by heterozygous mutation in the RAC3 gene (602050) on chromosome 17q25.

Clinical Features

White et al. (2018) reported a girl (BAB8740) with global developmental delay, poor language, seizures, and thin corpus callosum on brain imaging. She had dysmorphic features, including midface hypoplasia, micrognathia, hypertelorism, long eyelashes, prominent eyes, anteverted nares, wide nasal bridge, short nose, long philtrum, and dental anomalies. She also had clinodactyly, fetal finger and toe pads, and genital hypoplasia. There was no family history of a similar disorder, and the authors suggested that her features were reminiscent of Robinow syndrome (see 180700).

Costain et al. (2019) reported 5 patients, including 2 maternal half sibs, with a similar neurodevelopmental disorder. They had global developmental delay with severely to profoundly impaired intellectual development, and abnormal muscle tone. Two patients had seizures and 3 had scoliosis. Brain imaging showed variable structural abnormalities in all patients, including absence of or thin corpus callosum, enlarged ventricles, and cerebral dysgenesis with polymicrogyria and heterotopia. The 2 half sibs had Chiari type I malformation. Dysmorphic features were nonspecific and variable: frontal bossing, brachycephaly with sloping forehead, prominent glabella, hypertelorism, narrow palpebral fissures, high-arched eyebrows, depressed nasal bridge with broad nasal tip, short philtrum, high-arched palate, dental crowding, simple ears, full lips, tapered fingers, and clinodactyly.

Molecular Genetics

In a girl with NEDBAF, White et al. (2018) identified a de novo heterozygous missense mutation in the RAC3 gene (A59G; 602050.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.

In 5 patients, including 2 half sibs, with NEDBAF, Costain et al. (2019) identified heterozygous missense mutations in the RAC3 gene (602050.0002-602050.0004). The mutations occurred de novo in 3 patients and were suspected to result from maternal gonadal mosaicism in the affected half sibs. The mutations, which were found by exome sequencing, were not present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated a toxic gain-of-function effect due to constitutive activation and abnormal GTPase signaling.