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Genetic epilepsy syndromes

Gene: RALA

Green List (high evidence)

RALA (RAS like proto-oncogene A)
EnsemblGeneIds (GRCh38): ENSG00000006451
EnsemblGeneIds (GRCh37): ENSG00000006451
OMIM: 179550, Gene2Phenotype
RALA is in 2 panels

5 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

https://www.biorxiv.org/content/biorxiv/early/2018/07/29/378349.full.pdf Not listed on OMIM. Pubmed ref to paper incorrect on panel app: 30500825. Hiatt et al, 2018 - intellectual difficulty, speech delay or no speech, problems with motor skills - like walking. 6/11 had seizures - 5 unrelated families - 2 of the probands are monozygotic twins. 8 de novo het missense variants, 1 de novo in frame del and a nonsense variant, functional work done.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intellectual disability and developmental delay

Eleanor Williams (Genomics England Curator)

Comment on publications: 10.1371/journal.pgen.1007671 is PMID: 30500825
Created: 22 May 2019, 3:48 p.m.

Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least seven apparetly gain of function variants identified in eleven unrelated cases, with seizures reported in six of these cases.
Created: 11 Dec 2018, 11:41 a.m.
Comment on publications: PMID for doi.org/10.1371/journal.pgen.1007671 not yet available
Created: 11 Dec 2018, 11:37 a.m.
Comment on list classification: Based on reviewers' comments and sufficient cases.
Created: 11 Dec 2018, 11:16 a.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA.

DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted.

RALA belongs to the RAS superfamily of small GTPases.

5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although apart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158.

Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears).

Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase).

Several lines of evidence are provided to show that alteration of the GTP/GDP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain.

For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS by the authors.

Seizures were a feature in most (6/11) individuals (5 different variants incl. R176X). Discordance for this feature was however noted for individuals with the same variant.

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Created: 1 Dec 2018, 11:37 a.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Seizures
  • Abnormality of nervous system morphology
OMIM
179550
Clinvar variants
Variants in RALA
Penetrance
unknown
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
Panels with this gene

History Filter Activity

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to RALA.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to RALA.

22 May 2019, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: RALA were set to doi.org/10.1371/journal.pgen.1007671

11 Dec 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Konstantinos Varvagiannis: Hiatt et al. (doi.org/10.1371/

11 Dec 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

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

11 Dec 2018, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: RALA were set to

11 Dec 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

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

1 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: RALA was added gene: RALA was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology Penetrance for gene: RALA were set to unknown Mode of pathogenicity for gene: RALA 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: RALA was set to GREEN