Inheritance

Autosomal recessive

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Tandem repeat expansion - Variable repeats in intron 2

• Repeats

  • Expansion hunter AARRG

  • Can be variable AAGGG,ACAGG,AGGGC,AAGGC,AGAGG (STRchive)

  • May be flanked by other motifs. Motif heterogeneity is common in unaffected individuals.

  • Normal min range is not well defined. Leaving undefined

    • From Stripy: In one study of 608 controls, 75% had the reference (AAAAG)₁₁ allele and 13% carried an expanded (15-200 repeats) version of the same repeat. In 8% of cases there was an expansion (400-1000 repeats) of another (AAAGG) motif. Finally, four individuals had expansions in the range of 40-1000 repeats of the pathogenic (AAGGG) motif, which, however, was in the heterozygous state and therefore not pathogenic. In addition, some healthy individuals also had biallelic expansions of different repeat unit combinations, either (AAAAG)_exp/(AAAGG)_exp, (AAAAG)_exp/(AAGGG)_exp or (AAAGG)_exp/(AAGGG)_exp, demonstrating that only biallelic expansions of AAGGG are disease-causing (Cortese et al., 2019).”

  • PATH MIN: ≥ 400

Review:

• STRchive - normal max 11, path min 400

• Stripy - Pathogenic ≥ 400

• gnomAD - Pathogenic ≥ 400

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

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