Early onset or syndromic epilepsy

Gene: RAC3

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Comment on list classification: There are now at least 14 patients from 13 unrelated families with de novo heterozygous variants in this gene (PMIDs: 29276006; 30293988; 35851598; 35595279). Seizures reported in at least 8 individuals. Therefore, this gene can be promoted to Green at the next GMS panel update.

Created: 10 May 2023, 2:17 p.m. | Last Modified: 10 May 2023, 2:17 p.m.

Panel Version: 4.33

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Comment on list classification: Gene status was changed to Green due to a expert review by Konstantinos Varvagiannis. Sufficient unrelated individuals, from two publications to classify RAC3 as Green. There is no phenotypes associated in OMIM, but is probable in Gene2Phenotype with appropriate phenotype.

Created: 30 May 2019, 12:43 p.m. | Last Modified: 17 Jul 2019, 1:14 p.m.

Panel Version: 0.200

Green List (high evidence)

PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients.

All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance).

Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family.

Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006).

As a result, this gene can be considered for inclusion in the ID panel as green (or amber).
Sources: Literature

Created: 9 Oct 2018, 8:04 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability

Publications

• 30293988
• 29276006

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments