Inheritance

Autosoma dominant

Prevalence

 1-9 / 100 000

Source: ORPHA:98755

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none; GenCC - Ambry (Moderate), BabySeq - None, HGMD - 3 entries for SCA type 1.

Clinical Validity Scoring Notes and points

8358429 - age of onset in two families with SCA1 is 4-70 years. Per text the affected individuals are from 5 different SCA1 families, and they had DNA from 58 of the affected individuals, all who had expanded TaqI fragments. Per table 1, they show the affected and unaffected individuals that underwent PCR analysis of the CAG repeat, based on this info, counting 31-5= 26 segregations, 3 POINTS SEG. Repeats for unaffected ranged from <29 to 36, affected individuals 43 to >60. Anticipation observed in the two kindreds with earlier AOO. Counting 0.5 points for each proband’s expansion variant as well (0.5*5=2.5 VARIANT POINTS).

15148151 (Brusco 2004) - 225 unrelated Italian probands with hereditary ataxia. SCA1 identified in 48 probands with 37-60 repeats found (table 2). Normal range is noted to be 6-44 with repeats 39-50 pathogenic only if uninterrupted. The SOP doesn’t really account for how to score for STRs, will count another 2 VARIANT POINTs to be conservative

30391819 (Zhang 2019) - 35 repeats probable shortest pathogenic allele for SCA1. 17 patients from 1 family in China with SCA and a dominant inheritance pattern.

7647801 - immunoblot showed ATXN1 protein expressed in nuclei in neurons of basal ganglia, pons, and cortex, and cytoplasm and nuclei of Purkinje cells of cerebellum 1 POINT EXPERIMENTAL EXPRESSION

10624951 - In HeLa cells, the mutant protein with an expanded polyglutamin tract was 3 times more resistant to degradation, and 12757932 - mutant ATx1 forms aggregates in Drosophila 1 POINT BIOCHEMICAL FUNCTION

7553854 - Transgenic mice with either normal or expanded CAG tract. Those with expanded SCA1 developed ataxia and Purkinje cell degeneration. 12086639 - Mice with a 154 CAG repeat insertion developed a progressive neuro disorder that resembel SCA1 - 3 POINTS ANIMAL MODEL

Clinical Validity Points Total

12.5 POINTS

Clinical Validity Classification

Definitive

Source: 8358429, 15148151, 7647801, 10624951, 12757932, 7553854, 12086639.

Molecular Mechanism

NOT LOF - no LOF variants in HGMD. Suspected GOF - polyQ expansion alters ATXN1 conformation and enhances the strength of interaction with ATXN1 partners (PMID: 31655597)

Triplet repeat expansion of CAG in exon 8 (first coding exon) of ATXN1. Pathogenicity and risk for expansion depend on whether CAT interruptions are present.

• Normal: 6-35 with CAT interruptions

• Mutable normal (ie - premutation allele with normal phenotype but can expand to path range): 36-38 without CAT interruptions

• Full penetrance:

  • ≥39, but between 39-44 is pathogenic only if there is an uninterrupted stretch of CAG of at least 39 repeats.

CUTOFF: 36 (note we will review many of these as there are ~1000 alleles in gnomAD in the 36-39 range)

Sources: 20301363, 11973625, 23935513

Literature

gnomAD - Normal ≤ 32, Intermediate 36 - 38, Pathogenic ≥ 39

GeneReviews - Normal 6-36. Pathogenicity in 36-44 range is dependent on the presence of CAT intteruptions. Those without interruptions are mutable normal (36-38) or full penetrance >39. Reduced penetrance - 44. Full penetrance 39-44 must be uninterrupted. 46-70 uninterrupted repeats with CAT interruptions and additional CAGs reported.

Mayo paper (https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149 - Expanded: >38 (Uninterrupted) or >43 (Interrupted), cutoff 36

• 11973625 - Analyzed repeat length and composition of SCA1 gene in 15 individuals with intermediate alleles from 36-41 repeats. Alleles with 35-38 triplets were present in individuals with ataxia but no additional features of SCA1. 39 uninterrupted repeats observed with typical SCA1.

• 23935513 - 36 individuals with SCA1 studied to understand sequence and length variations. Most frequent uninterrupted sequence was (CAG)47, and most frequent interrupted allele sequences were [(CAG)12(CAT)(CAG)(CAT)(CAG)14] and [(CAG)12(CAT)(CAG)(CAT)(CAG)15]. Interruptions were present in both normal and path alleles. All the patients with interruptions had a stretch of at least 39 unintterrupted CAGs. One had alleles with the following pattern (CAG)_19–20(CAT)(CAG)(CAT)(CAG)_17–19 but was found to have a repeat expansion in ATXN3.

• 30108484 - Examined 6378 SCA1 chromosomes, report a very late onset SCA1 family with an uninterrupted 38 repeat allele.

https://www.sciencedirect.com/science/article/abs/pii/S0197458017303822?via%3Dihub

Penetrance

(list source/PMID)

High

Source: 20301363 (reduced penetrance has been reported)

Age of Onset

(list source/PMID)

Adulthood (typically 3rd or 4th decade, though childhood and late-adulthood have been reported)

Source: 20301363

Severity

Moderate

Clinical Features

cerebellar ataxia

dysarthria, deterioration of bulbar function

Early in disease - gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia

Later signs - slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia

Advanced stages of disease - muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction

Source: 20301363

HPO Terms

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

Gene SOPs & Notes

Caused by triplet repeat expansion with interruptions

Curation Summary

The ATXN1 gene is associated with autosomal dominant spinocerebellar ataxia type 1, which is characterized by cerebellar ataxia, dysarthria, bulbar dysfunction, ocular manifestations such as hypermetric saccades and nystagmus, and cognitive dysfunction. It is caused by a short tandem repeat expansion of CAG in the coding region of the gene. PMID: 20301363.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 09.11.2023 https://broadinstitute.atlassian.net/browse/BCL-168