Inheritance

Autosomal dominant

Prevalence

 1-9 / 100 000

Source: ORPHA:98756

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - not present (under review by ALS GCEP). GenCC - Definitive by Ambry. BabySeq - not present. HGMD -

Clinical Validity Scoring Notes and points

Classic SCA2:

• 10735276 (Riess 1997) - 842 patients with sporadic ataxia and 96 families with dominant SCA who were negative for SCA1 and SCA3. An expansion in SCA2 was found in 71 patients from 54 families with repeats sized 36–64. 241 healthy individuals over 85 were used as controls, the most common repeat length was 22 in this group, and the longest was 31. Unaffected relatives of individuals with SCA were also studied, the repeat range in this group was 17-31 repeats. Paternal anticipation was observed. Age of onset was inversely correlated to length of repeat. Counting 6 VARIANT POINTS from this study (kind of like a case control).

• 9158145 (Cancel 1997) - 184 probands with AD cerebellar ataxia screened for CAG repeat. Expansion found in 109 patients from 30 families. Affected individuals had 34-57 CAG repeats without interruptions, and all normal chromosomes were 14-31 repeats in length and had 1-3 interruptions of CAA. Counting another 6 VARIANT points here (a bit arbitrary since the SOP doesn’t account for STR disorders, also using the max points for a case-control study). Also, there are clearly segregations here in this data, but not shown.

• 10973246 (Huynh 2000) 0 Mice expressing ataxin-2 with Q58 showed progressive functional deficits accompanied by loss of Purkinje cell (measured by clasping, stride length, and rotarod testing). Human brains showed cytoplasmic microaggregates of SCA protein. 23087021 - another transgenic mouse model showed reduced Purkinje cell firing and motor deficits at 8 weeks of age and reduced Purkinje cell numbers at age 12 weeks. 1 POINT FXNL PATIENT CELLS, 2 POINTS MOUSE MODEL.

• 21307863 (Sun 2011) - Large Chinese family with Parkinsonism and SCA symptoms. Segregations shown in fig 1. Counted 1 proband and 13 segregations (including obligate carriers III-3, III-5, III-10, and II-2). 2 POINTS SEGREGATION, Reproduced over time

Infantile-onset (caused by large expansions >200 repeats)

• 21880993 - 6 patients with very large SCA2 expansions >200 repeats who presented in infancy with hypotonia, global DD, infantile spasms, and retinitis pigmentosa.

• 9779806 - >200 repeats identified in infant with neonatal hypotonia, DD, Dysphagia, RP. Father had mild SCA first noted at 22 years.

• 23047744 - Large expansion reported in an patient with infantile onset. At 6 months, observed to have little eye contact, uncoordinated eye movement, lack of head control, hypotonia, myoclonic jerks and athetoid movements. Abnormal EEGPallor of optic nerves and hyperpigmentation of dystrophic retinae. The father was affected with SCA and had an expanded allele.

• 32870233 - An expansion of ~884 repeats found in a patient with nystagmus at 3 months, ataxic gait, delayed speech, dysarthria, poor coordination, dysphagia, generalized spasticity, mild pontine atrophy, moderate cerebellar atrophy. The mom was similarly affected, at 7 years walking and speech difficulties, seizures at 10years, and at age 27 had ataxia, dysarthria, dysmetria, dysdiadochokinesia,

• 12116207 - Infantile/juvenile cases reported. Case 16, 11 month old with severe hypotonia, fhx of SCA2, and 230 repeats. Case 21 - 10 month old with hypotonia, DD, dysphagia, Fhx of ataxia and 400 repeats. Case 24 is a 3 month old with encephalopathy, chronic seizures, family history of SCA2 and 350 repeats. Case 25 - 10 month old with hypotonia, visual impairment, family history of SCA2 and 500 repeats.

Clinical Validity Points Total

17 points

Clinical Validity Classification

Definitive

Source: 10735276, 9158145, 10973246, 23087021, 21307863

Molecular Mechanism

Not caused by LOF variants (none associated with SCA in HGMD). Likely gain-of-function (PMID: 30588499)

Triplet repeat expansion - CAG repeat in exon 1 of the coding region of ATXN2.

• Normal ≤31

• Intermediate/reduced penetrance: 32-34

• Pathogenic: ≥33

• PROPOSED CUTOFF 32.

gnomAD - There are 22 alleles in the intermediate range of 32-34, and 2 above 35 repeats.

Stripy - Normal 13-31, Intermediate 32-34, pathogenic ≥35

MAYO cWGS validation https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149 Expanded: ≥33, Cutoff 32

GeneReviews PMID: 20301452 - Normal 31 or fewer. ALS risk alleles 30, 31, 32 repeats. Recessive 31/31 repeats. Pathogenic dominant alleles are 33 or more repeats. Reduced penetrance alleles 33-34. Full penetrance 37-39 repeats. Large repeats >200 have been reported. Interruption by CAA does not mitigate pathogenicity of the repeat, but it could aid meiotic stability. L-dopa therapy has been reported to be successful in several individuals.

34010218 (Laffita-Mesa 2021) - Review. ≥32 repeats cause disease. Clinical features - progressive gait ataxia, dysarthria, dysphagia, cognitive decline, slow eye movements, ophthalmoplegia, Parkinsonism, pyramidal features, and/or neuropathy. Intermediate repeats ≥29CAG/CAA repeats increase risk for other neurological diseases.

9158145 (Cancel 1997) - 184 probands with AD cerebellar ataxia screened for CAG repeat. Expansion found in 109 patients from 30 families. Affected individuals had 34-57 CAG repeats without interruptions, and all normal chromosomes were 14-31 repeats in length and had 1-3 interruptions of CAA.

21934711 (Laffita-Mesa 2012) - Nationwide study of ATXN2 in Cuba where SCA2 is more common. Most common allele in the population was 22 repeats. Range 13 to 31. Intermediate alleles 32-33 repeats were also found a high frequency in Cuban chromosomes (equal frequency as 28 and 31 repeats observed) at approx 0.5%. Only two intermediate alleles were observed in affected individuals, both with 32 repeats. Alleles that were 27-31 in length were somatically unstable, suggest that 27 may be a more appropriate threshold for intermediate alleles.

Penetrance

(list source/PMID)

Moderate (33-34 repeats), Complete (>34 repeats)

Source: 20301452

Age of Onset

(list source/PMID)

Typically adulthood, but large expansions can result in infantile / pediatric onset.

Severity

Moderate to severe

Clinical Features

Classic SCA2 features: progressive gait ataxia, dysarthria, dysphagia, cognitive decline, slow eye movements, ophthalmoplegia, Parkinsonism, pyramidal features, and/or neuropathy

Sources: 34010218, 20301452

Infantile/Juvenile features: Hypotonia, seizures, visual impairment, developmental delay, encephalopathy.

Sources: 21880993, 9779806, 23047744, 32870233, 12116207

HPO Terms

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

Gene SOPs & Notes

 Triplet repeat expansion, see molecular mechanism.

Curation Summary

The ATXN2 gene is associated with autosomal dominant spinocerebellar ataxia type 2, which is characterized by progressive gait ataxia, dysarthria, dysphagia, cognitive decline, slow eye movements, ophthalmoplegia, Parkinsonism, pyramidal features, and/or neuropathy (PMID: 34010218, 20301452). It is caused by a triplet repeat CAG expansion in exon 1 of the gene. Onset is typically in adulthood; however, large expansions have been reported in individuals with infantile or pediatric onset with additional clinical features including hypotonia, seizures, visual impairment, developmental delay, and encephalopathy (PMID: 21880993, 9779806, 23047744, 32870233, 12116207). In addition, intermediate repeat alleles have been associated with an increased risk of amyotrophic lateral sclerosis (PMID: 20740007, 21670397 21562247, 37146135, 35896380)

Case ID, Curator name, Date, Jira ticket link

Inheritance

Increased risk

Prevalence

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - not present (under review by ALS GCEP).

Clinical Validity Scoring Notes and points

20740007 (Elden 2010) - Case-control study. Proposed that intermediate length alleles over 23 CAG repeats may be associated with ALS. Compared 915 subjects with ALS with 980 neurologically normal subjects. 4.7% of the ALS cohort had repeats 27-33 in length, whereas only 1.4% of controls had expansions, p=3.6x10-5, OR =2.8 (95%CI 1.54-5.12). TARDBP gene, encoding TDP-43, has also been linked to familial ALS, and Ataxin-2 was suggested to be a modulator of the TDP43 protein, which is why they investigated ATXN2 repeats.

21670397 (Daoud 2011) - Case-control study. 556 ALS patients and 471 controls. 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. CAG repeats of 29 or higher were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). Association was stronger for familial cases.

21562247 (Van Damme 2011) - 1845 sporadic and 103 familial ALS cases and 2002 controls from Belgium and Netherlands. Found association between ALS and repeats 29 or more (OR, 1.92; p = 0.036). The greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036).

37146135 (Henden 2023) - assessed 21 STRs in WGS data using ExpansionHunter, REViewer, and PCR from 608 patients with sporadic ALS, 68 patitients with sporadic FTD, and 4703 matched controls. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. 48 patients with sALS carried known mutations in SOD1, TARDBP or repeat expansions in C9orf72. Intermediate ATXN2 expansions were three times more common in patients with sALS compared to controls (1.97% versus 0.66%, P = 0.0025, OR 3.01… no CI shown).

35896380 (Grassano 2022) - Population based cohort study of Italian ALS patients to investigate genetic causes. 26% received a genetic diagnosis in one of the several genes investigated. Intermediate-length ATXN2 CAG expansion (30–33 repeats) was the only high-risk genetic factor (defined as OR ≥2.0) identified in our cohort (OR 2.84, 95% CI 1.45 to 5.57, p=0.0023). The ATXN2 expansions were present in 41 (3.9%) patients.

Clinical Validity Points Total

Clinical Validity Classification

Molecular Mechanism

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

HPO Terms

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

Gene SOPs & Notes

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Inheritance

Prevalence

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - not present (under review by ALS GCEP).

Clinical Validity Scoring Notes and points

Based on below evidence, lumped into SCA2 curation. The very large expansions are inherited from parents that have classic SCA2 presentation, and the infantile/juvenile onset features are very similar (hypotonia, visual impairment/RP, seizures/myoclonic jerks/abnormal EEG, developmental delay.

21880993 - 6 patients with very large SCA2 expansions >200 repeats who presented in infancy with hypotonia, global DD, infantile spasms, and retinitis pigmentosa.

9779806 - >200 repeats identified in infant with neonatal hypotonia, DD, Dysphagia, RP. Father had mild SCA first noted at 22 years.

23047744 - Large expansion reported in an patient with infantile onset. At 6 months, observed to have little eye contact, uncoordinated eye movement, lack of head control, hypotonia, myoclonic jerks and athetoid movements. Abnormal EEGPallor of optic nerves and hyperpigmentation of dystrophic retinae. The father was affected with SCA and had an expanded allele.

32870233 - An expansion of ~884 repeats found in a patient with nystagmus at 3 months, ataxic gait, delayed speech, dysarthria, poor coordination, dysphagia, generalized spasticity, mild pontine atrophy, moderate cerebellar atrophy. The mom was similarly affected, at 7 years walking and speech difficulties, seizures at 10years, and at age 27 had ataxia, dysarthria, dysmetria, dysdiadochokinesia,

12116207 - Infantile/juvenile cases reported. Case 16, 11 month old with severe hypotonia, fhx of SCA2, and 230 repeats. Case 21 - 10 month old with hypotonia, DD, dysphagia, Fhx of ataxia and 400 repeats. Case 24 is a 3 month old with encephalopathy, chronic seizures, family history of SCA2 and 350 repeats. Case 25 - 10 month old with hypotonia, visual impairment, family history of SCA2 and 500 repeats.

Clinical Validity Points Total

n/a

Clinical Validity Classification

LUMPED INTO SCA2. See lit notes in clinical validity scoring section.

Molecular Mechanism

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

HPO Terms

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

Gene SOPs & Notes

Curation Summary

Case ID, Curator name, Date, Jira ticket link