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Gene-disease assertions not curated here (add link or write note): Leigh Syndrome (Limited by ClinGen)

Disease

Acute Necrotizing Encephalopathy (ANE)

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

  • Family 671: 0.5 points c.2085C→T; p.Thr653Ile

  • Family 613: 0.5 points c.2094A→G; p.Ile656Val

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

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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