Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Definitive (Ambry), Strong (Invitae)

Clinical Validity Scoring Notes and points

Kobayashi 2011 PMID: 21683323

• Linkage in 3 unrelated Japanese families (LOD of 4.6) mapped to the gene. Expansion showed complete segregation.

• Repeat sizes ranged from 3 to 8 in 300 Japanese controls

• Cases had expansions that were no smaller than 1500 repeats (see supplement), Expansions ranged from approximately 1500-2500 in 27 cases.

• No association between length of repeat and age of onset, no obvious anticipation observed in the pedigrees.

• Decreased expression in spinal tissue observed. Immunoblotting confirmed the presence of Nop56 in neural tissues.

• Patients RNA expression and protein levels appeared normal in LCLs, indicating that haploinsufficiency is not the mechanism.

• Proposed toxic gain of function

Lam 2023 PMID: 37810464

• Analyzed 1257 British patients with hereditary ataxia and 7506 controls.

• Normal alleles 3-14 hexanucleotide repeats

• Expanded alleles range from 30-2500 (most between 650 and 2500). It isn’t 100% clear what the smallest expanded allele is so I would use 650.

Baviera-Munoz 2023 PMID: 37332636\

• NOP56 expansion identified in 37 individuals from 16 apparently unrelated families from a Spanish cohort with cerebellar ataxia.

• Not clear what the size of the expansions are.

Wang 2022 pMID: 36368168

• Case report and review. Cites normal range as 3-14 repeats. Expanded as 650-2500.

• Case report here describes expanded allele in this family as 782 repeats

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Short Tandem Repeat - GGCCTG in intron 1

• Normal ≤ 14

• Pathogenic ≥ 650

Cutoff: 15

PMID: 21683323, 37810464

Review:

• STRchive - Normal: 3-14, Intermediate 15-649, Pathogenic 650-2500

• GnomAD - Normal ≤ 14, Pathogenic ≥ 650

• Nirvana - Normal 0-14, Expanded 15-inf

• STRipy - Normal 3-14, Pathogenic ≥25

• Mayo - not available

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Average in the 5th or 6th decade (PMID: 37810464)

Severity

Clinical Features

Cerebellar ataxia

• Dysarthria, dysphagia, vertigo, upper and lower motor neuron signs

Cerebellar atrophy

Hearing loss

Sources: 37810464, 37332636

HPO Terms

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

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.13.24 https://broadinstitute.atlassian.net/browse/BCL-168