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

Disease

Huntington disease

Inheritance

Autosomal dominant (due to triplet repeat expansion with paternal anticipation)

Prevalence

 1/20, 000-1/10,000

Source: ORPHA:399

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD

ClinGen General Gene Curation GCEP, accessed 8.22.2023

Clinical Validity Scoring Notes and points

The HTT gene was first reported in relation to Huntington disease (MONDO:0007739, MIM #143100) in 1993 (PMID: 8458085). While many affected individuals present during the fourth or fifth decade of life, onset can occur as early as 2 years (PMID: 15338298, PMID: 32998776) or as late as 80 years of age (PMID: 10644798). All affected individuals harbor an in-frame expansion of a trinucleotide repeat (CAG) near the 5’ end of the coding region of the HTT gene, with the number of CAG repeats correlating inversely with age of onset. Patients frequently present with progressive neuromuscular phenotypes ranging from gait disturbance and bradykinesia to chorea, ataxia, abnormal saccadic eye movements, and dystonia. Common neurological features range from cognitive impairment and speech impairment to seizures and progressive neurodegeneration. Examination of the brain typically reveals neuronal intranuclear inclusions, neuronal loss, and selective brain atrophy (especially within the caudate nucleus and putamen). Genotyping of the HTT locus within affected tissues generally reveals evidence of further somatic expansion of the CAG repeats from the pathogenic allele. Ten suspected pathogenic variants were scored as part of this curation, all of them in-frame insertions of additional CAG codons within a trinucleotide repeat microsatellite near the 5’ end of the HTT coding region. These variants have been sorted into two separate groups; one with the total number of CAG repeats >40 (completely penetrant), and the other with the total number of CAG repeats falling between 36 and 39 (associated with incomplete penetrance). These variants have been collectively reported in ten unrelated probands in six publications (PMID: 32998776, PMID: 15338298, PMID: 26300964, PMID: 29036832, PMID: 10644798, PMID: 8311509). All ten probands were heterozygous for their respective variants. Abundant segregation evidence was available from the literature (including PMID: 2571579, PMID: 3017842, PMID: 29956026), maxing out the total number of points for segregation evidence. The mechanism of pathogenicity appears to be monoallelic gain of function, characterized by abnormal nuclear localization and aggregation of the expanded HTT variant within neuronal cells in affected tissues (PMID: 9267034, PMID: 9302293, PMID: 15654337). This hypothesized mechanism is consistent with the dose-dependent relationship between the degree of CAG expansion in the pathogenic allele and the phenotypic severity. Most individuals with Huntington disease harbor one variant allele within the HTT locus; however, affected individuals harboring homozygous HTT variants have also been reported in the literature, and exhibit severity and age of onset similar to their heterozygous siblings, indicating complete dominance of the variant allele (PMID: 2881213, PMID: 10051023). This gene-disease association is also supported by experimental evidence that the HTT protein product normally localizes to neuronal regions of the brain (PMID: 7820679, PMID: 7568002, PMID: 23715323). Variant HTT proteins with expanded glutamine repeats tend to form aggregates both in vitro and in vivo, particularly following protease cleavage (PMID: 9267034). Expanded HTT variant proteins also exhibit abnormal nuclear accumulation and defective nuclear export in both patient cells (PMID: 9302293) and non-patient cells (PMID: 15654337). Expression of a partial human HTT transgene with expanded CAG repeats in Drosophila photoreceptor cells triggers progressive degeneration and formation of nuclear inclusions within the photoreceptor cells (PMID: 9768849). Mouse expression of a similar partial human HTT transgene with approximately 150 CAG repeats recapitulates many of the progressive neuromuscular features of the human patients, as well as the dominant mode of inheritance, the somatic instability of the transgene itself, and the formation of neuronal intranuclear inclusions (PMID: 9267033, PMID: 8898202, PMID: 9020849). Many of these findings have been independently confirmed in other reports, and additional available experimental evidence (PMID: 32444599, PMID: 9874792) was not scored since maximum scoring in this category had already been reached. In summary, HTT is definitively associated with Huntington disease. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification.

Source: ClinGen General Gene Curation GCEP, accessed 8.22.2023

Clinical Validity Points Total

17.5

Source: ClinGen General Gene Curation GCEP, accessed 8.22.2023

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: ClinGen General Gene Curation GCEP, accessed 8.22.2023

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Gain of function

Triplet repeat expansion - CAG in exon 1

  • Normal: ≤26 repeats

  • Intermediate/Premutation: 27–35 repeats

    • Can expand to pathogenic range in successive generation

    • Typically associated with a normal phenotype, but rare instances of genomic instability causing mosaicism and expansion into path range, which can lead to clinical features

  • Pathogenic incomplete penetrance: 36–39 repeats

  • Pathogenic complete penetrance: ≤40

  • Adenine interruptions: Loss of interrupting (LOI) adenine nucleotides in the (CAG)n-CAA-CAG region (penultimate CAA interrupting the CAG repeats) is associated with earlier age of onset and increased penetrance in individuals with 36-39 repeats (PMID: 31104771, 31607598

Source: PMID: 34413240, 28817209 30419368 General Gene Curation GCEP, accessed 8.22.2023

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Moderate to complete (dependent on length of repeat)

*Note: Could not find exact % of the penetrance for the incomplete penetrance alleles,

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Pediatric to late adulthood

Dependent on length of repeat, with longer repeats associated with earlier onset.

Source: 30419368

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

Pathogenic alleles are caused by triplet repeat expansion of CAG in exon 1 of HTT. Note that the pure CAG repeat (CAG copy number, Q1) is followed immediately downstream by an additional glutamine encoding CAA-CAG cassette (Q2). The standard approach to genotyping in HD is to use PCR and fragment length to infer the number of pure CAGs and assume the typical allele structure, and report on the total glutamines (ie - Qt = Q1 + Q2) PMID: 31607598.

The number of CAG repeats is measured as the number of uninterrupted CAG repeats, and this is what is used as a result of the test (ie - do not count the CAA-CAG). 22990145

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-dsiease relationship is limited

Case ID, Curator name, Date, Jira ticket link

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