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Intellectual disability syndromic and non-syndromic

Gene: RAC1

Green List (high evidence)

RAC1 (Rac family small GTPase 1)
EnsemblGeneIds (GRCh38): ENSG00000136238
EnsemblGeneIds (GRCh37): ENSG00000136238
OMIM: 602048, Gene2Phenotype
RAC1 is in 6 panels

1 review

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

At least 7 individuals reported so far, all variants missense, most de novo. Hotspot/cluster in GTP binding motif.1 paper postulated toxic GoF as the mechanism of disease (PMID: 30293988), however another suggested LoF, and functional studies have yet to be performed in patient cells (PMID: 30042656). Phenotypic variability may be related to mutational mechanism.
The phenotype was highly variable: 1 patient had an IQ of 35 at age 13, several had poor or absent speech, and several had delayed or impaired walking. Other neurologic features included poor feeding, hypotonia (in 4 patients), seizures (3), behavioral problems (3), and stereotypical movements (3). Four patients had microcephaly (-2.5 to -5 SD), 1 was normocephalic, and 2 had macrocephaly (+4.16 and +4.5 SD). Most patients had dysmorphic facial features, although there was not a common recognizable gestalt. Features included arched eyebrows, dysplastic ears, prominent nasal bridge, upturned nose, overhanging columella, long palpebral fissures, and broad or open mouth. One patient had sensorineural hearing loss and mild visual impairment. Brain imaging was abnormal in all 6 patients who were studied, although these findings were also highly variable. Common abnormalities included cerebellar hypoplasia, cerebellar dysplasia, hypoplasia of the corpus callosum, enlarged ventricles, mega cisterna magna, and thin brainstem. One patient had polymicrogyria. The 2 patients with macrocephaly had only nonspecific periventricular white matter lesions. Other less common extraneurologic features included hypospadias, cardiac abnormalities, recurrent infections, and eczema.
Created: 6 Aug 2020, 7:53 a.m. | Last Modified: 6 Aug 2020, 7:53 a.m.
Panel Version: 0.2823

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation, autosomal dominant 48 617751

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Genetic Health Queensland
Phenotypes
  • Mental retardation, autosomal dominant 48, MIM# 617751
OMIM
602048
Clinvar variants
Variants in RAC1
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

6 Aug 2020, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: rac1 has been classified as Green List (High Evidence).

6 Aug 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48, MIM# 617751 to Mental retardation, autosomal dominant 48, MIM# 617751

6 Aug 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RAC1 were changed from Mental retardation, autosomal dominant 48 617751 to Mental retardation, autosomal dominant 48, MIM# 617751

6 Aug 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RAC1 were changed from to Mental retardation, autosomal dominant 48 617751

6 Aug 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: RAC1 were set to

6 Aug 2020, Gel status: 3

Set mode of pathogenicity

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of pathogenicity for gene: RAC1 was changed from to Other

6 Aug 2020, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: RAC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

22 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: RAC1 was added gene: RAC1 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: RAC1 was set to Unknown