Hereditary neuropathy or pain disorder

STR: ATXN1_CAG

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.

Created: 25 Aug 2026, 2:24 p.m. | Last Modified: 25 Aug 2026, 2:41 p.m.

Panel Version: 8.32

Publications

• 39289638
• 25344417
• 36618024
• 8619528

Green List (high evidence)

The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.

Created: 25 Feb 2025, 10:30 a.m. | Last Modified: 25 Feb 2025, 10:30 a.m.

Panel Version: 6.151

ATXN1_CAG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.

Created: 21 Oct 2024, 3:40 p.m. | Last Modified: 21 Oct 2024, 3:40 p.m.

Panel Version: 5.24

Phenotypes
Ataxia neuropathy syndromes

STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.

Created: 15 Mar 2022, 11:41 a.m. | Last Modified: 15 Mar 2022, 11:41 a.m.

Panel Version: 1.441

Green List (high evidence)

Green rating for STR submitted on behalf of James Polke (North Bristol NHS Trust), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 29 Apr 2019, 9:47 a.m.

Green List (high evidence)

Comment when marking as ready: Marked as ready following the Webex discussion with experts from the GMCs (6/09/2018) about feeding back STR results

Created: 5 Dec 2018, 10:51 a.m.

Added to the panel following the Webex discussion with experts from the GMCs (6/09/2018) about feeding back STR results
Sources: Expert Review

Created: 5 Dec 2018, 10:51 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this STR are reported as part of current diagnostic practice

Interruptions in the repeated sequence are reported as part of standard diagnostic practise