Inheritance

Autosomal dominant

Prevalence

 Unknown

Source: ORPHA:276244

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - no curations yet. GenCC - Definitive (LMM), Strong (Ambry). BabySeq - none. HGMD - All SCA/MJD variants are repeat variations.

Clinical Validity Scoring Notes and points

7874163 (Kawaguchi 1994) - First paper to identify CAG expansions. Nine patients from 7 Japanese families had expansions between 68-79 repeats. Inverse relationship between length of repeat and age of onset. Fig 9 shows repeat number from 72 normal health Japanese controls, max normal repeat was 37. From fig 7, counting 3 segregations. 7x0.5= 3.5 VARIANT POINTS

36247768 (Lan. 2022) - 30 Taiwanese patients with hereditary spastic paraplegia. Three patients with repeats sized 83, 67, and 72. All individuals had cerebellar ataxia as part of the study inclusion criteria. In addition, these individuals per table 1 had dystonia, ophthalmoplegia, polyneuropathy and parkionsonism. 3x0.5 = 1.5 VARIANT POINTS

32488064 - See supplement table S1. Patients 29 - 38 with 64, 63, 71, 71, 62, 62, 62, 63, 67, and 66 repeats. All with family history reported. These are patients reported previously in Kawaguchi, Okamoto et al. 1994.

7655453 (Schols 1995)- German cohort of patients with SCA. 30 patients from 19 families found to have an expansion between 67-78 repeats. Fig 1 shows normal repeat sizes, max was 28. Unfortunately they don’t show any segregations, though there must be at least 11 based on the ext description (30 patients from 19 families). 19x0.5= 5.5 VARIANT POINTS, 11 segs.

10.5 VARIANT POINTS

2 SEGREGATION POINTS (14 segs, using incomplete penetrance and heterogeneity AD calculation)

2 POINT MOUSE MODELs:

• 11978767 - Transgenic mouse. Mice with expanded alleles showed a progressie cerebellar deficit as early as 4 weeks. With disease progression, pelvic elevation became flattened and was accompanied by hypotonia and motor/sensory loss. Neuronal intranuclear inclusion formation and cell loss was prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Peripheral nerve demyelination and axonal loss was also detected in symptomatic mice from 26 weeks of age. Disease seereity increased with level of expression.

• 19666958 - Conditional mouse model. Transgenic mice showed progressive neurologic phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired performance on the rotarod test, and lower body weight gain. Symptoms were reversed when ataxin-3 expression was turned off in symptomatic mice.

Source:

Clinical Validity Points Total

14.5 points

Source: 7874163, 36247768, 7655453, 11978767, 19666958

Clinical Validity Classification

Definitive

Source: 7874163, 36247768, 7655453, 11978767, 19666958

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Triplet repeat expansion of CAG in the 3' coding region

• Normal 12-40

• Intermediate (incomplete penetrance and unstable repeats): 45-55

• Pathogenic: 61-87

• Proposed cutoff: 41

Literature notes:

Primary lit repeat sizes summarized here: https://docs.google.com/spreadsheets/d/1VM18JjKe_GyaLBIyCnP9Jbh4X0WN49qFKTqBjbuU-dQ/edit#gid=0 Repeats over 61 are clearly pathogenic based on the below papers and those above in the clinical validity scoring section of this curation. Uncertainty as to the smallest known full penetrance pathogenic allele. Limited number of individuals reported in the intermediate range, though there is some evidence that when present homozygous or biallelic state they can cause disease. I would consider those of uncertain significance for heterozygotes. I had a hard time finding primary literature that supports the cutoffs reported in GeneReviews and Stripy. Suggest using 45 as the cutoff since it is consistent with Mayo, GeneReviews, and Stripy.

https://stripy.org/database/ATXN3 - Normal 12-44, Intermediate 45-55, Pathogenic ≥56

gnomAD - Normal ≤ 44, Intermediate 45 - 55, Pathogenic ≥ 56

GeneReviews - Normal 12-44, Intermediate (incomplete penetrance and/or unstable repeats): 45-55, Pathogenic full penetrance: 60-87

37088140_S13 - Mayo’s cWGS validation paper, they set their cutoff at 45, defined Expanded: >59, Intermediate: 45-59

15457499 - 3 generation family with SCA3. The proband had gait ataxia at 65. Staring look, cerebellar dysarthria, broken saccadic and puruit eye movements. Dystonia, brisk deep tendon jersk. had a repeat of 45. It expanded to 47 to son, and contracted when inherited by proband’s grandson.

30131520 - Review, lists the intermediate range as 45-55 and disease range as 56-86.

31669734 - Review. Affected individuals repeat range from 56-87, and incomplete peentrance from 45-55. Same authors as 30131520. Cites below papers for these repeat sizes:

• 17390258 - Review, describes normal as 12-40 and disease range as ~60-84. Describes a mother daughter pair with repeats of 54 and 52.

• 7611296 - DNA samples from 212 individuals from 33 MJD families. Unaffected individuals had allele sizes from 12-37. MJD carriers have alleles in the expanded range of 62-84 repeats.

• 7633439 - 90 MJD individuals from 62 families. Disease alleles were 61-84, normal were 14-34.

• 8619527 - 64-82 repeats observed in mutation carriers (99 affected and 27 asymptomatic carriers. Normal chromosomes from unrelated unaffected controls and normal chromosomes from patients and at risk carriers was between 14 and 40.

• 15316156 - Chinese kindred with SCA. Proband presented with a dominant family history, ataxia, nystagmus, abnormal eye movements, autonomic dysfunction. Allele size was found to be 51, which is shortest known causative expanded allele. An affected sib had 55 repeats, and a first cousin had 63.

• 11409435 - Dutch family in which 4 members in 2 generations have intermediate repeats of 53 and 54. Clinical features included restless leg syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Proband is a 66yo man with trembling hands and legs, unsteady gait and calf cramps at 53. Slight mask facies, moderate resting and postural tremor in arms and postural tremor in trunk, head and upper legs. Locomotor disability due to abnormal gait.

22133674 - Review. Describes pathogenic range as ~60-87.

24450306 - 158 subjects belonging to 21 Azorean MJD families. Patients had 61–80 repeats. Normal alleles were 13-28.

21743138 - can’t access, per HGMD “Spinocerebellar ataxia; 49-86 repeats.”

Compound hets reported in HGMD, did not fully review: 27896316 (Cerebellar ataxia with sensory neuropathy; Two compound heterozygotes for intermediate alleles (55/49 in both cases). Unaffected family members have 50/7 and 57/21 repeats.) 32643267 (55-67 repeats in homozygous patients.) 29801869 - homozygous SCA patients. repeats from 57-72.

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Adolescence to adulthood

Source: PMID: 20301375

Severity

Moderate

Clinical Features

Progressive cerebellar ataxia

Dysarthria

Ophthalmic involvement - Nystagmus; slow saccadic eye movements; ophthalmoparesis, dysconjugate eye movements, & diplopia

Vestibular dysfunction

Motor neuron degeneration (hyperreflexia, spasticity, fasciculation, weakness w/ muscule wasting, areflexia, distal sensory loss.

Dystonia

Parkinsonism - often DOPA responsive

Autonomic dysfunction - Bladder disturbances, difficulty w/thermoregulation, & cardiovascular dysautonomia

Sources: PMID: 20301375

HPO Terms

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

Gene SOPs & Notes

Triplet repeat disorder, see molecular mechanism section.

Curation Summary

The SCA3 gene is associated with autosomal dominant spinocerebellar ataxia type 3, also known as Machado-Joseph syndrome. It is characterized by progressive cerebellar ataxia, dysarthria, ophthalmic involvement, motor neuron degeneration, dystonia, Parkinsonism, and autonomic dysfunction (PMID: 20301375). It is caused by a triplet repeat CAG expansion in the coding region of the gene. In addition, biallelic cases have been reported (PMID: 27896316, 32643267).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 09.14.2023 https://broadinstitute.atlassian.net/browse/BCL-168