ORPHA: 659609;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.3 | Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies | 618577 | Autosomal dominant | 3 | RAC3 | 602050 |
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.
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, broad 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.
Scala et al. (2022) reported 10 patients with NEDBAF, including the patient initially reported by White et al. (2018). Neurologic findings in the patient cohort included hypotonia (93.7%), seizures (43.7%), dyspraxia (40%), and spasticity (25%). Microcephaly was seen in 12.5% of patients and abnormal head shape was seen in 31.2%. Of the 10 patients who had brain imaging, 10 had abnormalities in the corpus callosum, 9 had global reduction in the brain volume, 7 had malformations of cortical development, 6 had cerebellar dysplasia, and 5 had brainstem anomalies. Feeding difficulties were common (62.5% of patients). Other clinical features in a subset of patients included respiratory issues, joint laxity, and nystagmus.
The heterozygous mutations in the RAC3 gene that were identified in patients with NEDBAF by White et al. (2018) and Costain et al. (2019) occurred de novo.
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.
Scala et al. (2022) identified heterozygous mutations in the RAC3 gene in 10 unrelated patients with NEDBAF, including the patient initially reported by White et al. (2018). Eight individual mutations were identified (602050.0001 and 602050.0004-602050.0009) and all were shown to be de novo. Expression of RAC3 with each of the mutations in cultures of primary mouse hippocampal neurons resulted in neurons with less neurite expression and rounding of the cell body compared to controls. The GDP/GTP exchange rate and GTP hydrolysis activity were tested in recombinant RAC3 with each mutation, with differences in effects on exchange rate and hydrolysis rate compared to wildtype among the mutations. Scala et al. (2022) concluded that biochemical differences among the mutants variously dysregulates RAC3 function in vivo with possible associated clinical implications.
Costain, G., Callewaert, B., Gabriel, H., Tan, T. Y., Walker, S., Christodoulou, J., Lazar, T., Menten, B., Orkin, J., Sadedin, S., Snell, M., Vanlander, A., 9 others. Do novo missense variants in RAC3 cause a novel neurodevelopmental syndrome. Genet. Med. 21: 1021-1026, 2019. [PubMed: 30293988] [Full Text: https://doi.org/10.1038/s41436-018-0323-y]
Scala, M., Nishikawa, M., Ito, H., Tabata, H., Khan, T., Accogli, A., Davids, L., Ruiz, A., Chiurazzi, P., Cericola, G., Schulte, B., Monaghan, K. G., and 34 others. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes. Brain 145: 3308-3327, 2022. [PubMed: 35851598] [Full Text: https://doi.org/10.1093/brain/awac106]
White, J. J., Mazzeu, J. F., Coban-Akdemir, Z., Bayram, Y., Bahrambeigi, V., Hoischen, A., van Bon, B. W. M., Gezdirici, A., Gulec, E. Y., Ramond, F., Touraine, R., Thevenon, J., and 24 others. WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome. Am. J. Hum. Genet. 102: 27-43, 2018. [PubMed: 29276006] [Full Text: https://doi.org/10.1016/j.ajhg.2017.10.002]