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

Disease

ATXN8OS-related spinocerebellar ataxia

Inheritance

Autosomal dominant

Prevalence

Unknown

Source: ORPHA:98760

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - no curations. GenCC - no curations. BabySeq - no curations. HGMD - 5 variants, all are repeat variants.

Clinical Validity Scoring Notes and points

Koob 1999 PMID: 10192387 - 8 pedigrees with AD SCA studied and found CTG repeat expansions. One was a large family with 84 members who were clinically evaluated, linkage provided a max lod score of 6.8. (3 POINTS SEGREGATION) 20 individuals with an expanded repeat were not clinically affected. All but 1 individual with a CTG repeat of more than 107 repeats are affected. This individual was 42 and had 140 CTG repeats. 99% of alleles from a general population cohort of 1200 alleles were 16-37 repeats in size, though there were some identified that were up to 91 repeats. Among ataxia patients from the large SCA8 kindred, alleles ranged from 110 to 130 combined CTA/CTG repeats (107−127 CTG repeats alone). PCR of cDNA indicates expression in whole brain tissue, but not heart, placenta, liver, skeletal muscle, kidney or pancreas. There were two individuals who were homozygous for the expansion.

Moseley 2000 PMID: 10958651 - Large family reported in Koob was studied and they found 6 different sequence configurations of the CTG repeats. The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n. The CTG portion of the repeat is elongated on pathogenic alleles. Expanded alleles were found to either have a pure uninterrupted CTG repeat or an allele with one or more CCG, CTA, CTC, CCA, or CTT interruptions. They also observed that the repeat tract in sperm underwent contractions, which they suggest could underlie reduced penetrance w/ paternal transmission.

Moseley 2006 PMID: 16804541 - Transgenic mice with the expansion, but not controls, develop a progressive neurological phenotype with imaging showing reduced cerebellar-cortical inhibition. Intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein. Encoded on a previously unidentified antiparallel transcript spanning the repeat in the CAG direction. Expression of noncoding CUGn expansion transcripts (ATXN8 opposite strand, ATXN8OS)

Hannan 2018 PMID: 30443043

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

Proposed Gain of function due to repeat expansion (PMID: 20301445)

Triplet repeat expansion - (CTA·TAG)n(CTG·CAG)n

  • Variability in the normal, intermediate, expanded ranges as described in the different sources below. Reduced penetrance described. Needs further review for what we would use.

  • GeneReviews (PMID: 20301445) - Normal 15 to 50 (CTA·TAG)n(CTG·CAG)n repeats. Reduced Penetrance occurs for repeats of all sizes. Pathogenic (higher penetrance) 54 to 250 (CTA·TAG)n(CTG·CAG)n

  • gnomAD - Normal ≤ 37, Intermediate 38 - 79, Pathogenic ≥ 80 (consistent w/ Stripy database)

  • STRchive: https://github.com/hdashnow/STRchive/blob/main/data/STR-disease-loci.json - "normal_min": "15", "normal_max": "50", "intermediate": "50-70", "intermediate_min": "50", "intermediate_max": "70", "pathogenic": "71-1300". Cites Hannan 2018, Mirkin 2007, GeneReviews, \"SourceId\": \"NBK535148\", s40478-021-01201-x",

  • Mayo - no info https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149

  • Stripy - Normal 2-37, Intermediate 38-79, Pathogenic >80

  • Nirvana annotation - 0-50, 51-inf (repeat unit is CTA) → For this reason, I don’t think we can use Nirvana to identify expansions in this gene, as the other sources (gnomAD, STRchive) use the CTG.

Daughters 2009 (PMID: 19680539) -

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)

Adulthood (3rd to 5th decade)

PMID: 20301445

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.

Moderate

Clinical Features

Progressive ataxia

Scanning dysarthria, slowness of speech

Gait instability

Eye movement abnormalities - nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia

Upper motor neuroon involvemnent

Extrapyramidal signs

Brainstem signs (dysphagia and poor cough reflex

Sensorineuropathy

Cognitive impairment - executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some

Normal lifespan

Sources: PMID: 20301445

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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