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Gene-disease assertions not curated here (add link or write note):

Disease

Spinocerebellar ataxia

Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Strong (Invitae). BabySeq - none. HGMD papers below.

Holmes 1999 PMID: 10581021

  • A large pedigree with SCA. Onset ranged from 8-55y. All 10 living affected family members had an expansion. Unexpanded alleles were <29 repeats. Expanded were >65. In 394 healthy controls, the unexpanded alleles ranged from 7-28.

Wang 2011 PMID: 21743138

Brusco 2004 PMID: 15148151

Rossi 2019 PMID: 31190316

Wan 2021 PMID: 34284285

Clinical Validity Scoring Notes and points

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

Short Tandem Repeat - CAG repeats in the 5’UTR

Review:

  • Stripy - Normal: 7-31. Pathogenic ≥51

  • STRchive - Normal 4-32. Pathogenic ≥51

  • gnomAD Normal 4-32. Pathogenic ≥51

  • Depienne (review) PMID: - Normal 4-32, pathogenic ≥43-78.

  • Mayo - none

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

Most individuals present in the fourth decade with upper extremity tremor, progressing over several decades to include head tremor, gait ataxia, dysmetria, dysdiadokinesis, hyperreflexia, paucity of movement, abnormal eye movements and, in the oldest subjects, dementia. Cortical and cerebellar atrophy on MRI/CT in some - PMID: 10581021

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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