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Gene-disease assertions not curated here (add link or write note):

Disease

Huntington disease-like 2

Inheritance

Autosomal dominant

Prevalence

 <1/1,000,000

Source: Orphanet

Rapid or full curation?

  • Rapid
  • Full

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, eLOD 3.612, 2 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

12 POINTS

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: 26079385, 11694876

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

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

26079385)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

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 BCL-168 - Getting issue details... STATUS

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