Early onset or syndromic epilepsy

Gene: RALA

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

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

Comment on publications: 10.1371/journal.pgen.1007671 is PMID: 30500825

Created: 22 May 2019, 3:48 p.m.

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.

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