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Genetic epilepsy syndromes

Gene: RNF13

Amber List (moderate evidence)

RNF13 (ring finger protein 13)
EnsemblGeneIds (GRCh38): ENSG00000082996
EnsemblGeneIds (GRCh37): ENSG00000082996
OMIM: 609247, Gene2Phenotype
RNF13 is in 3 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:39 a.m. | Last Modified: 9 Sep 2019, 10:39 a.m.
Panel Version: 1.320
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

I don't know

AD EIEE73. Edvardson et al, 2019 (30595371) - 3 unrelated children with a severe neurodev and neurodegen disease. They developed refractory, tonic-clonic and myoclonic seizures between 7 weeks and 7 months of age. All had de novo het missense variants -L311S (patient 1 - died at 33 months) and L312P (patients 2 and 3 - both still alive at 8 years and 21 months respectively). These variants are localised in a highly conserved sequence, AA 309-319 are the target of post-translational modification by phosphorylation.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

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

Catherine Snow (Genomics England)

Comment on mode of pathogenicity: Selected other as mode of pathogenicity as authors are predicting activating mechanism rather than LOF
Created: 27 Jun 2019, 9:02 a.m. | Last Modified: 27 Jun 2019, 9:02 a.m.
Panel Version: 0.31
RNF13 identified by expert review by Konstantinos Varvagiannis. Edvardson et al. (PMID: 30595371) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants. All individuals had seizures from a young age 7 weeks - 7 months. Two distinct variants identified. Variants are reported to not be LOF but hypothesised that gain of function mechanism. Therefore as mechanism unclear, only one case report in the supplementary material, limited phenotype evidence for the additional two affected individuals and that this is the first time of RNF13 being reported in literature, classifying RNF13 as Amber and adding to watch list for more evidence to be reported. Is probable in Gene2Phenotype.
Created: 27 Jun 2019, 8:48 a.m. | Last Modified: 15 Jul 2019, 9:32 a.m.
Panel Version: 0.72

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants.

Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment.

One individual harbored the p.Leu311Ser variant (NM_007282.4:c.932T>C) while 2 others the p.Leu312Pro (c.935T>C).

RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor.

The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser:
- Protein levels were similar to controls upon Western blotting in patient fibroblasts.
- Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function.
- Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders.

Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed.

Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones).
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RNF13 is not associated with any phenotype in OMIM, nor in G2P.
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As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature
Created: 30 Dec 2018, midnight

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

Phenotypes
Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment

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 Amber
  • Expert Review
  • Expert Review Amber
  • Expert Review
Phenotypes
  • Cortical visual impairment
  • Failure to thrive
  • Seizures
  • Congenital microcephaly
  • Epileptic encephalopathy, early infantile, 73
  • Abnormal muscle tone
  • Feeding difficulties
  • Intellectual disability
  • Global developmental delay
  • Sensorineural hearing impairment
OMIM
609247
Clinvar variants
Variants in RNF13
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

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to RNF13.

17 Sep 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to RNF13.

22 Jul 2019, Gel status: 2

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review was added to RNF13. Source Expert Review Amber was added to RNF13. Added phenotypes Epileptic encephalopathy, early infantile, 73 for gene: RNF13 Publications for gene RNF13 were changed from to 30595371 Rating Changed from No List (delete) to Amber List (moderate evidence)

30 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: RNF13 was added gene: RNF13 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment Penetrance for gene: RNF13 were set to unknown Mode of pathogenicity for gene: RNF13 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: RNF13 was set to GREEN