Early onset or syndromic epilepsy
Gene: RNF13Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).Created: 20 Oct 2020, 3:59 p.m. | Last Modified: 20 Oct 2020, 3:59 p.m.
Panel Version: 2.196
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.
Panel Version: 2.491
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies. Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).Created: 23 Mar 2020, 5:11 p.m. | Last Modified: 30 Mar 2020, 1:19 p.m.
Panel Version: 2.25
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Three unrelated individuals with de novo gain-of-function variants in this gene reported; severe neurodegenerative disorder, seizures are a prominent part of the phenotype.Created: 25 Jan 2020, 3:35 a.m. | Last Modified: 25 Jan 2020, 3:35 a.m.
Panel Version: 2.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Epileptic encephalopathy, early infantile, 73, MIM# 618379
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
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
Agree there are 3 unrelated cases - so reclassify as greenCreated: 27 Apr 2022, 9:35 a.m. | Last Modified: 27 Apr 2022, 9:35 a.m.
Panel Version: 2.518
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
Comment on mode of pathogenicity: Selected other as mode of pathogenicity as authors are predicting activating mechanism rather than LOFCreated: 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
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: LiteratureCreated: 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
Phenotypes for gene: RNF13 were changed from 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 to Developmental and epileptic encephalopathy 73, OMIM:618379
Tag for-review was removed from gene: RNF13.
Source Expert Review Green was added to RNF13. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: RNF13.
Gene: rnf13 has been classified as Green List (High Evidence).
Source Wessex and West Midlands GLH was added to RNF13.
Source NHS GMS was added to RNF13.
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)
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