Inheritance

Autosomal dominant

Prevalence

 “Acute necrotizing encephalopathy type 1 is likely a very rare condition, although its incidence is unknown. At least 59 cases of this condition have been reported in the scientific literature.”

Source: MedlinePlus

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen: This gene-disease association is not in ClinGen, although there is a curation for RANBP2 - Leigh syndrome.

GenCC:

• Strong for AD familial acute necrotizing encephalopathy by Invitae

• Limited for AD familial acute necrotizing encephalopathy by G2P

BabySeq: Absent.

HGMD:

• DM: Encephalopathy, acute necrotising

• DM?: Increased risk of neurodevelopmental disorder, Autism spectrum disorder, Miscarriage, Hypoplastic left heart syndrome, Atypical cerebral palsy, Primary biliary cholangitis. Congenital heart disease, Psychiatric disorder.

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

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

RANBP2 c.1754C>T p.T585M

• REVEL: 0.178

• 2 alleles in GnomAD v4.

• PMID: 19118815: 35 unrelated families with clinical dx of ANE. This variant was identified in 9 of the families. Haplotype analysis was done and 7 families showed unique haplotypes, so only including those 7 families:

  • Descr. as c.1880C/T, p.Thr585Met.

  • Familial cases (total 3.5 points)

    • Family 586: 0.5 points

    • Family 102: 0.5 points

    • Family 112: 0.5 points

    • Family 105: 0.5 points

    • Family 670: 0.5 points

    • Family 690: 0.5 points

    • Family 119: 0.5 points

• PMID: 19811512: 9 yo Caucasian female with rapid-onset severe encephalopathy triggered by viral infections. MRI characteristic of ANE during both episodes.

  • Mother had an episode of ‘encephalitis/polyneuritis’ after having a viral infection at the age of 19 years; she has had a foot drop since then.

  • Variant identified in proband and mother, de novo in mother.

  • Reported as c.1880C→T.

  • 0.5 points (not counting mother since phenotype is unclear/unconfirmed)

• PMID: 34377735: 9 month old female with seizure and 4 day hx of fever. EEG was consistent with encephalopathy. MRI suggestive of possible acute viral encephalitis.

  • Identified RANBP2 (c.1754C>T; p.Thr585Met) on an epilepsy panel. Parents not tested.

  • 0.5 points

• PMID: 37090838: Two Brazilian families with ANE and c.1754C > T (p.Thr585Met) (total 1 point)

  • Family 1 (0.5 points)

  • Family 2 (0.5 points)

• PMID: 26923722

  • Patient P1, 10 month old boy with ANE confirmed on MRI.

  • p.Thr585Met identified, inherited from healthy father. (0.5 points)

• Other reports of this variant were present but not reviewed. From HGMD, PMIDs: 21945312, 25128471, 24321870, 25522933, 27591117, 28336122, 29741717, 29687329, 31589614, 30796099, 32760653, 33879512, 34059398, 33777149, 33761695, 34400285, 33726816, 35870896.

RANBP2 c.1958C>T p.Thr653Ile

• REVEL: 0.178

• Absent from GnomAD.

• PMID: 19118815:

  • Descr. as c.2085C/T, p.Thr653Ile.

  • Family 671: 0.5 points

• PMID: 25170550

  • 28 month old with ANE, confirmed on MRI.

  • Older sister died at 6 months within 12 hours of presenting with fever and seizures.

  • Father, paternal grandmother, and deceased sibling also had the same variant.

  • “DNA from the index case was sequenced” - not sure what method was used, it seems like the authors may have looked at RANBP2 specifically.

  • 0.5 points.

RANBP2 c.1966A>G p.Ile656Val

• REVEL: 0.306

• 1 allele in GnomAD v4

• PMID: 19118815:

  • Descr. as c.2094A→G; p.Ile656Val

  • Family 613: 0.5 points

• PMID: 36029610

  • Identified p.I656V in the homozygous state in a patient with ANE on WES. A sibling was also affected but DNA could not be tested. Both sibs died before reaching 1 yo.

  • Parents were heterozygous, unaffected.

  • Consanguineous family.

  • 0.5 points

RANBP2 c.2043G>C p.Trp681Cys

• REVEL: 0.460

• Absent from GnomAD v4.

• PMID: 26923722

  • Patient P2 with multiple episodes of ANE.

  • De novo missense mutation p.Trp681Cys in exon 14 of RANBP2. (1 point)

RANBP2 c.5249C>G Pro1750Arg

• One case report where authors suspect digenic inheritance, not counted (PMID: 32102593)

RANBP2 c.1350A>T p.Leu450Phe

• Seen in 6 individuals in GnomAD v4.

• REVEL: 0.0570

• PMID: 34377735: 6yo female with acute encephalopathy with seizures, MRI and EEG findings, and negative autoimmune, metabolic, infectious and toxic workup. Encephalopathy panel returned RANBP2 p.Leu450Phe, reported as a VUS.

• Not counting due to higher AF and very low REVEL score.

Segregation Evidence:

RANBP2 c.1754C>T p.T585M

• REVEL: 0.178

• 2 alleles in GnomAD v4.

• PMID: 19118815: 35 unrelated families with clinical dx of ANE. 35 unrelated families with clinical dx of ANE. This variant was identified in 9 of the families. Haplotype analysis was done and 7 families showed unique haplotypes, so only including those 7 families:

  • Descr. as c.1880C/T, p.Thr585Met.

  • Familial cases (incomplete penetrance, phenocopies present - used calculator) (total 1 point)

    • Family 586: 8 segregations (1 point)

    • Family 102: 1 segregation (0 point)

    • Family 112: 0 segregations (0 points)

    • Family 105: 1 segregation (0 points)

    • Family 670: 1 segregation (0 points)

    • Family 690: 1 segregation (0 points)

    • Family 119: 0 segregations (0 points)

• PMID: 37090838: Two Brazilian families with ANE and c.1754C > T (p.Thr585Met)

  • Searched for variants in RANBP2 specifically and identified this. (total: 0 points)

  • Family 1 (0.5 points): 3 segregations (0 points)

  • Family 2 (0.5 points): 0 segregations (0 points)

Variant/Case Evidence: 9 points (so far)

Segregation Evidence: 1 point (so far)

Case/Control Evidence: N/A

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

~40%

Source: PMID: 19811512

Age of Onset

(list source/PMID)

Severity

Clinical Features

Triggered by febrile viral illness, causing acute encephalopathy 1-3 days following the onset of the infection. This may include “deteriorating consciousness, with rapid progression to coma, and can be accompanied by seizures and focal neurologic deficits” (PMID: 32426208). Recurrent episodes are common.

Sources: PMID: 32426208

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

https://docs.google.com/document/d/1XY2_T3IJ7mtVPSrC6dCWmV2gqgqJ2p1laVBGZySK7vM/edit

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Case ID: SDSM-8F

Areesha Salman, 12/14/2023