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Dystonia, chorea or related movement disorder, adult onset v6.9 ATXN1_CAG Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years, and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.
Dystonia, chorea or related movement disorder, adult onset v6.9 ATXN1_CAG Eleanor Williams Publications for STR: ATXN1_CAG were set to
Dystonia, chorea or related movement disorder, adult onset v6.8 ATXN1_CAG Eleanor Williams edited their review of STR: ATXN1_CAG: Added comment: Review of the mode of inheritance for this STR to check for any reported biallelic cases:

4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1)

PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected.

PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity.

PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined.
Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41)

PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients.

Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut:
- 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996)
- 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined).
- 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996)

Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; Changed publications to: 39289638, 25344417, 36618024, 8619528
Dystonia, chorea or related movement disorder, adult onset v3.7 ATXN1_CAG Eleanor Williams commented on STR: ATXN1_CAG
Dystonia, chorea or related movement disorder, adult onset v3.7 ATXN1_CAG Eleanor Williams Classified STR: ATXN1_CAG as Green List (high evidence)
Dystonia, chorea or related movement disorder, adult onset v3.7 ATXN1_CAG Eleanor Williams Str: atxn1_cag has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, adult onset v3.6 ATXN1_CAG Eleanor Williams Tag watchlist was removed from STR: ATXN1_CAG.
Tag Q3_23_promote_green was removed from STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v3.4 ATXN1_CAG Sarah Leigh Tag Q3_23_promote_green tag was added to STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v3.4 ATXN1_CAG Sarah Leigh reviewed STR: ATXN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, adult onset v1.170 ATXN1_CAG Eleanor Williams Tag for-review was removed from STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.166 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Dystonia, chorea or related movement disorder, adult onset v1.162 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Dystonia, chorea or related movement disorder, adult onset v1.145 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Dystonia, chorea or related movement disorder, adult onset v1.144 ATXN1_CAG Arina Puzriakova Tag watchlist tag was added to STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.14 ATXN1_CAG Arina Puzriakova Tag for-review tag was added to STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Added comment: Comment on list classification: This STR has been temporarily downgraded from Green to Amber, and will be repromoted when this clinical indication moves to WGS.
Dystonia, chorea or related movement disorder, adult onset v1.6 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v0.93 ATXN1_CAG Louise Daugherty Source NHS GMS was added to STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v0.92 ATXN1_CAG Louise Daugherty commented on STR: ATXN1_CAG: Discussed with the GMS Neurology Specialist Test Group webex call 26th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this STR Green
Dystonia, chorea or related movement disorder, adult onset v0.87 ATXN1 Louise Daugherty commented on gene: ATXN1: New RED gene added from James Polke (Neurogenetics Laboratory, Institute of Neurology, London), this is likely to relate to the STR ATXN1_CAG and not the gene entity, as there are no SNVs for this gene being associated to the disorder, this gene is rated RED, the STR ATXN1_CAG is rated GREEN. To clarify with the Neurology Test Group in July 2019
Dystonia, chorea or related movement disorder, adult onset v0.33 ATXN1_CAG Louise Daugherty Classified STR: ATXN1_CAG as Green List (high evidence)
Dystonia, chorea or related movement disorder, adult onset v0.33 ATXN1_CAG Louise Daugherty Str: atxn1_cag has been classified as Green List (High Evidence).
Dystonia, chorea or related movement disorder, adult onset v0.32 ATXN1_CAG Louise Daugherty STR: ATXN1_CAG was added
STR: ATXN1_CAG was added to Adult onset movement disorder. Sources: Expert list
STR tags were added to STR: ATXN1_CAG.
Mode of inheritance for STR: ATXN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN1_CAG were set to Spinocerebellar ataxia 1 164400
Review for STR: ATXN1_CAG was set to GREEN
Added comment: Source PanelApp panels : Parkinson Disease and Complex Parkinsonism v1.64
Sources: Expert list