Inheritance

Autosomal dominant

Prevalence

 <1/1,000,000

Source: Orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen, BabySeq - no curations. Strong/Definitive in GenCC (Ambry and Invitae).

Clinical Validity Scoring Notes and points

PMID: 26079385 (2015)

• Triplet repeat expansion of CTG in exon 2 of JPH3. South African cohort referred for HD testing. 171 white and 130 black individuals. No white patients, but 15% of black patients (20/130) had an expansion in JPH3. 20*0.5=10 points

PMID: 11694876 (2001)

• 9 affected, 3 unaffected segregations,

PMID: 22447335

• More segregations - 7 affected (including 2 obligate carriers)

Seg total - 16 affected, 3 unaffected, eLOD 5.72, 3 points

There is also a mouse model, but I didn’t curate it as I reached 12 points (PMID: 16809425)

Source:

Clinical Validity Points Total

13 POINTS

Source:

Clinical Validity Classification

Definitive

Source: 26079385, 11694876

Molecular Mechanism

Mechanism unknown, but suggested due to Loss of function / Gain of function / Dominant Negative

Short tandem repeat expansion: CTG repeat in exon 2 (coding region)

• Normal: 6-26

• Uncertain (not described, other than personal obs in GeneReviews PMID: 20301701): 27-39

• Pathogenic: ≥40

• CUTOFF: 27

PMID: 11694876, 11694876, 20301701

Review:

• STRchive: Normal 6-28, Intermediate 29-39, Pathogenic 40-58

• GeneReviews PMID: 20301701: Normal 6-28. Alleles of questionable significance 29-39 (mutable normal or reduced penetrance), note this is a personal observation from the GeneREviews author. Full penetrance: 40 or more. Reduced penetrance described.

• STRipy: Normal: 6-27, Path ≥41

• GnomAD: Normal ≤ 27, Pathogenic ≥ 41.

• Mayo: none https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149

• PMID: 11694876 - Largest normal allele is 27. Smallest abnormal allele from affected - 41. But suggest expansions of “about 40 or more” cause HDL2.

• PMID: 26079385 - Expansions in affected individuals ranged from 40-58 repeats. expanded alleles were found on haplotypes originating from African origins. For normal controls, allele sizes ranged from 6 to 26 repeats, with no alleles observed between 19 and 21 repeats in either population (black or white controls)

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Typical: 30-52; Range: 12-66 (GeneReview). Inverse correlation between repeat length and age of diagnosis (PMID:

26079385)

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

The JPH3 gene is associated with autosomal dominant Huntington-disease like 2, which is caused by an expansion of a CTG repeat within the coding region of the gene. The disease is characterized by movement, emotional and cognitive abnormalities. Movement features include chorea, abnormal gait, oculomotor abnormalities, dysarthria, rigidity, and bradykinesia. Psychiatric disturbances include personality changes and depression, and cognitive abnormalities include progressive dementia. Brain MRI displays atrophy of the cuadate and cerebral cortex. Age of onset is typically in adulthood, with an average age of 41 years. There is an inverse correlation with age of onset and the length of the CTG short tandem repeat (PMID: 11694876, 11694876, 20301701, 26079385).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.07.24 https://broadinstitute.atlassian.net/browse/BCL-168