ATXN8OS (aka SCA8 or KLHL1AS) Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note): Parkinson disease
Disease | ATXN8OS-related spinocerebellar ataxia |
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Inheritance | Autosomal dominant |
Prevalence | Unknown Source: ORPHA:98760
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Rapid or full curation? | Rapid Full |
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. NORMAL MAX: 37; PATH MIN: 107 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 Stevanin 2000 PMID: 10700167 - 188 French controls and 250 European patients with ataxia. Observed bimodal distribution of (CTA)n/(CTG)n repeat numbers in ataxic patients. 487 chromosomes contained 2–25 repeats and 13 chromosomes (11 patients, including 2 homozygotes) contained 68–123 repeats. We found expansions of more than 91 (CTA)n/ (CTG)n repeats in 8 of 148 ADCA families, in an apparently sporadic ataxia patient, in a patient with neuropathologically confirmed Lafora disease and in a patient with familial essential tremor. Similarly, 99% of control alleles (n=373) carried 3–28 (CTA)n/(CTG)n repeats, except for 3 alleles with 107, 111 and 123 repeats from patients aged 57, 62 and 64 years, respectively (who were at least 20 years older than the mean age at onset reported for SCA8 patients2). Found interruptions in the CTG repeat tract. Largest pure CTG tract in a control was 107 and in an ataxia patient 109. NORMAL MAX 28, PATH MIN 109 (but decreased penetrance and interruptions) Chen 2015 PMID: 26112709 - In family I: 107 repeat in affected individual, 101 repeats in younger unaffected brother due to reduced penetrance. Normal repeat range given as 16-37, pathogenic repeat range given as 80-250. PATH MIN: 107 Aydin 2018 PMID: 29316893 - Pathogenic range between 116-129, one patient with 92. PATH MIN: 92 Koutsis 2012 PMID: 22297462 - case report, 81 repeats in affected individual (58yo with chorea, psych symptoms, cognitive decline). Onset in her 50s. PATH MIN: 81 Brusco 2004 PMID: 15148151 - 225 patients w/ dx of ataxia. Two families w/ an expansion. Family SCA8-MI-1 two siblings tested and had expansions ranging from 114 to 152 CTG+CTA. Second family SCA8-MI-2 only had the proband available, 139 CTG + CTA triplets ([CTG]128 + [CTA]11. Path min (CTG pure repeats) 111. Musova 2013 PMID: 22872568 - 515 with ataxia were studied. Friedreich ataxia, SCA1, SCA2, SCA3, SCA6, and SCA7 excluded. FMR1 excluded in all males over 50. Per table 1, smallest repeat is 71. Yamamoto-Watanabe 2010 PMID:
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Clinical Validity Points Total |
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Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
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Molecular Mechanism 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
Daughters 2009 (PMID: 19680539) - |
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) |
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Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adulthood (3rd to 5th decade) PMID: 20301445 |
Severity | 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 |
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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 |
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Case ID, Curator name, Date, Jira ticket link |
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