Inheritance

Autosomal dominant

Prevalence

 1-9 / 1 000 000

Source: ORPHA:94147

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - no curations. GenCC - Moderate (Ambry). BabySeq - none. HGMD - all SCA7 variants are repeat variations.

Clinical Validity Scoring Notes and points

9288099 (David 1997)- 18 patients from 5 families. All patients and two asymptomatic at risk subjects had expansions. Affected individuals had repeat sizes from 38-130, normal alleles was 7-17. Observed increases in CAG repeat in 13/14 parent child transmissions. Unfortunately the segregations aren’t clearly shown, but I think based on the numbers reported there are probably 13 (18-5), so being conservative and only counting half (6) Inverse correlation with age of onset and size of repeat observed. 5x0.5 = 2.5 VARIANT POINTS, 6 SEGS.

9425223 (Johansoon 1998) - Examined repeat lengths in 4 Swedish SCA7 families and 57 healthy controls. The repeat length in SCA7 patients ranged from 40 to >200 repeats. Controls had 7-15 repeats. Fig 4 shows 3 pedigrees, and table 1 shows clinical details and CAG repeat size. Same authors as 9288099, but counting segregation here since the evidence is a little clearer. Family A - 9 segregations. Family C, 1 segregation, Family D 1 segregation. 11 segregations total. 4X0.5 = 2 VARIANT POINTS, 11 SEGS (TOTAL 3 SEGREGATION POINTS)

23368522 (Magana 2014) - 10 families with SCA from Mexico and found55 patients with SCA7. Fig 2 shows several families with SCA7 and their repeat sizes. Family 1 is very large with many segregations. REPRODUCED OVER TIME

11580893 Transgenic mice expressing glutamine expansion had a cone-rod dystrophy phenotype, consistent w/ features of SCA7. 11030754 - Transgenic mice overexpressing full length mutant ataxin 7 with an expansion in Purkinje cells or rod photoreceptors have deficiencies in motor coordination and vision. 3 POINTS FOR MOUSE MODELS

23197655 - Reduction of mutant ataxin7 expression in mice restored motor fuunction and prevent cerebellar synaptic reorganization in a mouse model. 1 POINT RESCUE

11580893 - Northern blot showed that a 4.5kb transcript is predominantly expressed throughout CNS. Immunohistochemistry revealed intense cytoplasmic staining in cerebellar Purkinje cells, inferior olivary neurons, and retinal photoreceptor cells. 1 POINT EXPRESSION

Source:

Clinical Validity Points Total

12.5

Source: 9288099, 9425223, 23368522, 11580893, 11030754, 23197655, 11580893

Clinical Validity Classification

DEFINITIVE

Source:

Molecular Mechanism

Triplet repeat expansion of CAG in exon 3 (first coding exon)

• Normal: 7-27

• Mutable normal: 28-33

• Pathogenic

  • Reduced penetrance 34-36

  • Full penetrance ≥ 37

• Cutoff: 28

Mechanism is not LOF - no truncations in HGMD

Literature notes:

GeneReviews PMID: - Normal 7-27, Mutable normal 28-33, Pathogenic reduced penetrance 34-36, Pathogenic full penetrance 37-460.

Mayo cWGS validation paper - Expanded: >34, Reduced Penetrance: 34-36, Intermediate: 28-33. Cutoff 28

GnomAD - Normal ≤ 33, Intermediate 34 - 36, Pathogenic ≥ 37. Only 5 alleles ≥34 repeats.

9288099 (David 1997)- 18 patients from 5 families. All patients and two asymptomatic at risk subjects had expansions. Affected individuals had repeat sizes from 38-130, normal alleles was 7-17. Observed increases in CAG repeat in 13/14 parent child transmissions. Inverse correlation with age of onset and size of repeat observed.

9736784 (Stevanin 1998) - cites other studies

9425223 (Johansoon 1998) - Examined repeat lengths in 4 Swedish SCA7 families and 57 healthy controls. The repeat length in SCA7 patients ranged from 40 to >200 repeats. Controls had 7-15 repeats. Fig 4 shows 3 pedigrees, and table 1 shows clinical details and CAG repeat size. Family A - 9 segregations. Family C, 1 segregation, Family D 1 segregation. 11 segregations total.

9425222 (David 1998) - Analyzed repeats in 19 families and one isolated case. Repeats on normal alleles 7-35 CAGs. Most normal alleles were below 19 repeats. Only one individual had a repeat of 35, unaffected at 53, and it expanded to path range in children. Alleles in affected individuals 37-130.

10563484 - A woman with 34 CAG repeats had "very mild symptoms" at age 65 years, and another individual with 36 repeats had mild symptoms at 63 years.

9425905 - individual with 35 repeats described as affected (see fig 4a), but the clinical features aren’t very clear.

Penetrance

(list source/PMID)

Dependent on repeat size

Source: 20301433

Age of Onset

(list source/PMID)

Infantile to adult

Source: 20301433

Severity

Moderate to severe

Source: 20301433

Clinical Features

Progressive cerebellar ataxia (dysmetria, dysdiadochokinesia, and poor coordination)

Cone rod dystrophy

Motor neuron degeneration

Oculomotor abnormalities (slowed ocular saccades, ophthalmoplegia.

Infantile/early childhood onset: Failure to thrive, hypotonia, loss of motor milestones, rapid deterioration with early death)

Source: 20301433

HPO Terms

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

Gene SOPs & Notes

Triplet repeat disorder, see Molecular mechanism

Curation Summary

The ATXN7 gene is associated with autosomal dominant spinocerebellar ataxia type 7, which is characterized by progressive cerebellar ataxia, cone-rod dystrophy, motor neuron degeneration, and oculomotor abnormalities with onset in adolescence or adulthood. Infantile or early childhood onset has also been reported with clinical features including failure to thrive, hypotonia, loss of motor milestones, and other features of cerebellar and brain stem degeneration. It is caused by a triplet repeat expansion of CAG in the first coding exon of the ATXN7 gene.

Case ID, Curator name, Date, Jira ticket link

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