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

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

  c.2085C→T; p.Thr653IleFamily 613: 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.

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

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)

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

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)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

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

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link