Fetal anomalies
Gene: RAC3
The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 4:26 p.m. | Last Modified: 30 Jan 2023, 4:26 p.m.
Panel Version: 2.10
Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.Created: 5 Apr 2022, 4:38 p.m. | Last Modified: 5 Apr 2022, 4:38 p.m.
Panel Version: 1.850
This gene already has sufficient evidence for Green rating on the ID panel (see below) and now adding evidence (from NHS GMS testing) for prenatal phenotype to support Green rating for the Fetal Anomalies panel also: A RAC3 likely pathogenic missense variant has been identified postnatally in a baby that presented prenatally with absent corpus callosum, bilateral ventriculomegaly, cerebellar and brainstem hypoplasia detected on fetal ultrasound and MRI. The variant is judged by the child's clinical team to be causative of the clinical and radiological features in the child.
Copied from Green review on Intellectual Disability panel by Konstantinos Varvagiannis:
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).
Sources: Literature, Expert Review, NHS GMSCreated: 10 Feb 2022, 6:24 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag Q2_22_rating was removed from gene: RAC3.
Source Expert Review Green was added to RAC3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Gene: rac3 has been classified as Amber List (Moderate Evidence).
Tag Q2_22_rating tag was added to gene: RAC3.
gene: RAC3 was added gene: RAC3 was added to Fetal anomalies. Sources: Literature,Expert Review,NHS GMS Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAC3 were set to 30293988; 29276006 Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RAC3 was set to GREEN