Early onset or syndromic epilepsy

Gene: RANBP2

I don't know

Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy with seizures, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.

Created: 21 Nov 2025, 2:59 p.m. | Last Modified: 21 Nov 2025, 3:15 p.m.

Panel Version: 8.76

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.

RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025). RANBP2 association with familial acute necrotizing encephalopathy has been classified as Moderate in ClinGen by the Epilepsy Expert panel (April 2024) and Limited for Leigh Syndrome (Mitochondrial Diseases Expert Panel, June 2021).

Created: 21 Nov 2025, 2:44 p.m. | Last Modified: 21 Nov 2025, 2:47 p.m.

Panel Version: 8.74

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

Phenotypes
{Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033

Publications

• 34377735
• 36621064
• 38050538
• 40538544

I don't know

p.Thr585Met gnomAD frequency (1/245874) and seen in 9 of 15 families suspected of having familial or recurrent acute necrotizing encephalopathy. Potential risk factor. AD susceptibility to acute infection induced encephalopathy 3 (IIAE3). Molecular genetics on OMIM - Neilson et al 2009 - suggest that mutations in RANBP2 gene predispose to acute necrotising encephalopathy following febrile illness - but by themselves are insufficient to make the phenotype fully penetrant and additional genetic and environmental factors are required. In addition 4 more affected famiies did not carry RANBP2 mutations

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
{Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033

Publications

• 19118815

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: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information (e.g. on penetrance) is required for a clear gene:disease association.

Created: 25 Jul 2019, 3:28 p.m. | Last Modified: 25 Jul 2019, 3:29 p.m.

Panel Version: 1.181

Red List (low evidence)

We consider this a susceptibility gene, rather than a true monogenic condition, and as such would only analyse when specifically indicated based on presenting features and report only variants where increased risk is clearly established.

Created: 20 Aug 2018, 10:15 a.m.

The condition associated with RANBP2 is reported in gene reviews and other publications as monoallelic with incomplete penetrance
https://www.ncbi.nlm.nih.gov/books/NBK258641/
PMID: 25522933
PMID: 19118815

Created: 30 Sep 2017, 8:57 a.m.

Green List (high evidence)

Comment on publications: publications suggested by Andrea Haworth (ACGS, Congenica) as evidence for autosomal incomplete penetrance

Created: 9 Oct 2017, 10:42 a.m.

Comment on "Treatable" tag: Early diagnosis could allow potentially beneficial measures, such as ensuring up-to-date immunization status (eg, against influenza), though full protection against all inciting agents would not be possible

Created: 20 Mar 2017, 11:22 a.m.

Inclusion of this as a green gene on this panel is appropriate, based on the review in the Undiagnosed metabolic disorders panel and the views of clinical expert, Dr Arianna Tucci, UCL.

Created: 20 Mar 2017, 11:21 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033