Inheritance

Autosomal dominant

Prevalence

 Unknown

Source: ORPHA:98761

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none; GenCC - Ophanet (supportive); Babyseq - none; HGMD - 3 repeat variation variants listed with association to spinocerebellar ataxia 10.

Clinical Validity Scoring Notes and points

11017075 (Matsuura 2000)- A pentanucleotide expansion of ATTCT in intron 9 of the ATXN10 (aka SCA10) was identified in a large Mexican family with spinocerebellar ataxia. Affected individuals had repeats in the range of 800 to >3000A control cohort of 562 control chromosomes showed range of 10-22 repeats. Fig 1 shows PCR analysis performed in 4 families, counting 12 segregations here. Earlier age of onset observed in individuals with larger expansions (fig 4). Since repeat sizes are different in all 4 families, counting 0.5x4= 2 VARIANT POINTS

11506407 (Rasmussen (2001) - Author overlap with Matsuura 2000. Using table 2 and fig 1 to count affected segregations across the 4 families, also including obligate carriers. Family B: proband III-8. Segregations III-10, IV-1, obligate carriers II-1 and III-1 (4 segs). Family C: III-9 proband. Segregations III-14, IV-14, IV-24, IV-26, IV-28, IV-30, and obligate carrier III-12 (7 segs). Family D: II-3 proband. Segregations II-4, II-7, obligate carrier I-2 (3 segs). Family E - no segs can be counted. Total of 14 segregations across the 3 families.

24278426 (Bushara 2013)- An individual with Sioux Native American ancestry and features of spinocerebellar ataxia with an expanded allele of 1400. Age of onset 83 and authors suggest reduced penetrance. 0.5 VARIANT POINTS

28542277 (Naito 2017) - Japanese family with SCA type 10. Proband and her mother were genotyped and found to have an expanded allele. 0.5 VARIANT POINTS, 1 SEGREGATION.

17620556 (Gatto 2007) - Argentinean family with SCA. Can only count 1 segregation in figure.

31377949 (Dias Domingues 2019) - Brazilian families with SCA10. Based on Table 1, I think it is safe to assume there are several segregations, and only need to count 1 more to get to max segregation points combining with above papers. 1 segregation. There are 16 total probands with expansions >930, counting another 16x0.5 points for each proband variant. 8 VARIANT POINTS

26295943 - SMRT sequencing performed in three patients with known expansions in ATXN10.

Not scored: 23117922 - Expansion in ATXN10 observed in individual who also had SCA2 expansion, dual dx, did not score. 23083689 - dual dx of Huntington disease and SCA10

SEGREGATION - 17 total (reduced penetrance and phenocopies) = 3 POINTS

VARIANT - 11 POINTS

14 POINTS TOTAL

Clinical Validity Points Total

14

Source:

Clinical Validity Classification

DEFINITIVE

Source: 11017075, 11506407, 24278426, 28542277 17620556, 31377949

Molecular Mechanism

Likely gain-of-function (PMID: 36199580) Did not fully investigate mechanism, pathogenic variants are repeat expansions.

Repeat expansion in intron 9 of the ATXN10 gene. Typically pentanucleotide expansion of ATTCT.

• Normal: 9-32

• Intermediate (unknown significance, possibly reduced penetrance): 33-799

• Pathogenic: ≥800 (though lower limit is not very well defined and there could be overlap with reduced penetrance alleles, PMID: 20301354)

• INTERRUPTIONS: ATCCT interruption motif has been linked to risk for epileptic seizures (PMID: 24318420). Other interruptions have been reported, but exact impact isn’t well known.

• PROPOSED CUTOFF 33

Literature notes:

gnomad - very few alleles over 32 repeats

20931525 - Normal range of repeats was 9-32 in a Chinese healthy control cohort.

Mayo cWGS paper - https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149 ATXN10 gene not listed in table S23.

Reduced penetrance: 16717236 - A Brazilian family in which the affected proband had 400-repeat expansion, two unaffected sibs and her unaffected father had repeats f 370 and 360.

Interruptions:

• 36199580 (Kurosaki 2022) - Review. Normal length is 9-32 repeats. ATCCT interruptions appear to be a risk fator for an epileptic phenotype in SCA10. Expansions are frequently interrupted by ATCCT, ATCCC,ATTCC,ATTTCT,ATATTCT,ATTCTTCT, orATTCTTCT.

  • 24318420 (McFarland 2014)- ATCCT interruptions studied in a large cohort of SCA10 families. Found that presence of repeat interruptions confers a 6.3-fold increase in the risk of epilepsy and a 13.7-fold increase in having a positive family history of epilepsy. 31 SCA10 families, 5 with ATCCT interruptions. They found that repeat length did not correlate with epileptic seizures.

  • 23443018 (McFarland 2013) Same authors as above. 31 SCA10 families of Mexican, Brazilian, and Argentinean ancestry studied for ATCCT repeat interruptions. The expansion size was larger in patients with an interrupted allele, but no different in ageo of onset. Contractions of the repeats were observed in the presence of interruptions when paternally inherited. Paternally transmitted alleles also showed anticipation for both interrupted and non-interrupted expansions, however age of onset was earlier in the non-interrupted cohort.

• 36092952 (Morato Torres 2022)- Pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions reported in the same Mexican family. Found considerable mosaicism of the repeat expansion. Individuals with the mixed expansion showed signs of SCA, but of the 6 individuals with the pure expansion, 5 were unaffected and 1 presented with Parkinson disease at age 38. Two were passed the age of onset expected in this family by over 20 years. They propose that the pure ATTCTn expansion is non-pathogenic or has low penetrance with mild disease course.

15127363 - expanded alleles highly unstable when paternally transmitted

Penetrance

(list source/PMID)

Unknown (varies between length and presence of interruptions, few families to base penetrance off of).

Source: 20301354

Age of Onset

(list source/PMID)

Adolescence - Late Adulthood

PMID 20301354

Severity

Moderate

Clinical Features

Progressive cerebellar ataxia

Dysarthria, dysphagia

Nystagmus

Seizures, epilepsy

Sources: 20301354, 36199580

HPO Terms

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

Gene SOPs & Notes

Triplet repeat expansions, with interruptions, see molecular mechanism

Curation Summary

The ATXN10 gene is associated with autosomal dominant spinocerebellar ataxia type 10, which is characterized by Progressive cerebellar ataxia, dysarthria, dysphagia, nystagmus, and epileptic seizures (PMID: 36199580). It is caused by a short tandem repeat expansion in intron 9.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 9.12.2023 https://broadinstitute.atlassian.net/browse/BCL-168