Disease | Huntington disease-like 2 |
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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) PMID: 11694876 (2001) PMID: 22447335 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 | 12 13 POINTS Source: |
Clinical Validity Classification | Expand |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Definitive Source: 26079385, 11694876 |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| 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) 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)
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Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
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| 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 | Expand |
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| 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. |
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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 | Expand |
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| - 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 | Jira Legacy |
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| server | System Jira |
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| serverId | eee25142-2510-336f-918a-865682ebdf2e |
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| key | BCL-168 |
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