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?

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

Definitive

Source: ClinGen General Gene Curation GCEP, accessed 8.22.2023

Molecular Mechanism

Gain of function

Triplet repeat expansion - CAG in exon 1

• Normal: ≤26 CAG repeats

• Intermediate/Premutation: 27–35 CAG 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 CAG repeats

• Pathogenic complete penetrance: ≥40 CAG repeats

Juvenile HD typically occurs in the presence of ≥60 repeats

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, 31398342)

Source: PMID: 34413240, 28817209, 30419368

Penetrance

(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: PMID: 34413240, 28817209

Age of Onset

(list source/PMID)

Pediatric to late adulthood

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

Source: 30419368

Severity

Moderate

Clinical Features

• Progressive movement disorder: Chorea, bradykinesia, dystonia, tremor, rigidity, abnormal eye movement.

• Neuropsychiatric: Depression, anxiety, apathy, personality changes, behavior disturbances, obsessive compulsive disorder, psychosis, delusions

• Cognition: Cognitive deficits, dementia

• Other: Sleep disturbance

• Neuroimaging / neuropathology: Intraneuronal inclusions containing huntingtin, striatal atrophy, grey and white matter atrophy on MRI

Juvenile HD - Earlier onset of symptoms listed above, seizures, behavioral problems,

Sources: PMID: 34413240, 28817209, 20301482

HPO Terms

https://hpo.jax.org/app/

HP:0002072Chorea

HP:0002067Bradykinesia

HP:0001332Dystonia

HP:0001337Tremor

HP:0002063Rigidity

HP:0000496Abnormality of eye movement

Abnormal saccadic eye movements HP:0000570

HP:0000716Depression

HP:0000739Anxiety

HP:0000741Apathy

Personality changes HP:0000751

HP:0001250Seizure

HP:0200147Neuronal loss in basal ganglia

HP:0002067Bradykinesia

HP:0002066Gait ataxia

HP:0002059Cerebral atrophy

HP:0002500Abnormal cerebral white matter morphology

HP:0000726Dementia

HP:0000746Delusions

HP:0100785Insomnia

HP:0031589Suicidal ideation

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). However, 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). PMID: 22990145, 31398342

Curation Summary

The HTT gene is associated with Huntington disease, which is inherited in an autosomal dominant pattern with paternal anticipation. It is caused by a CAG triplet repeat expansion in exon 1 of the HTT gene, and is characterized by movement disorder, particularly chorea, and neuropsychiatric and cognitive changes. The HTT gene has also been reported in Lopes-Maciel-Rodan syndrome (PMID: 27329733, 36293294, 33432339, 26740508); however, evidence supporting this gene disease relationship is limited.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 08.23.2023,https://broadinstitute.atlassian.net/browse/BCL-168

Inheritance

autosomal recessive

Prevalence

Unknown;

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

Not in ClinGen; GenCC - Limited by Ambry https://search.thegencc.org/genes/HGNC:4851 ; not curated in BabySeq; HGMD: c.2114C>T p.P705L; c.2356C>T p.R786C IVS34 ds G-A +1

Clinical Validity Scoring Notes and points

26740508

• One proband compound het for two variants, but they both have a very high MAF considering this condition is purported to be very rare. Per SOP, not scoring this individual. Variants: c.2108C>T p.P703L (0.07%, 7/9986 AJ chr; 20/248284 total chr; very high frequency considering condition is purported to be extremely rare) and c.3779C>T p.T1260M (7.8%, 1335/16992 African/African American chr, 60 homozygotes.

27329733 - 2 POINTS

• One family with compound het variants in HTT identified via WES that segregate with disease. 1 proband, 2 affected siblings, 1 unaffected sibling. Variants confirmed in trans. 0 POINTS

• Clinical features severe, congenital neurodevelopmental disorder associated with central hypotonia, spastic quadraparesis, and variable dystonia, midline stereotypies, epilepsy, and high myopia.

• Variants

  • c.4469+1G>A (aka NM_002111.5: c.4463+1G>A), absent gnomAD, OOF exon, predicted loss of donor site. 2 POINTS

  • c.8156T>A (aka NM_002111.5(HTT):c.8150T>A p.F2717Y) absent gnomAD, conserved, but REVEL score 0.166 (does not meet scoring criteria) - 0 POINTS

36293294

• WES identified two variants in patient born preterm with DD, autism-like behaviors, stereotypies, and bruxism. Epileptiform activity on EEG, normal brain MRI.

• c.2350C>T Arg784Cys - 0.01% 2/17978 East Asian; 0.002% 7/249572 total chr. Seems too frequent to cause rare disorder (correlates to 1/2000 prevalence for AR) - 0 POINTS

• c.8440C>A Leu2814Met - absent gnomAD, REVEL 0.176 - 0 POINTS

33432339

• Reinvestigates family from PMID: 27329733. The c.4469+1G>A variant results in aberrant splicing of exon 34 and severely reduced mRNA (+0.5 POINTS). Phe2719Leu results in abnormally rapid turnover of the protein. +0.5 POINTS.

37199581

• FVB/N Mouse strain has seizures, study indicates that wt HTT protects neurons, since targeted inactivation of Htt (Htt+/- mice) have an increased frequency of seizure disorder, provide possible explanation for seizures in Lopes-Maciel-Rodan syndrome. Not really a mouse model for the condition however. Scoring at 0 points for now.

Clinical Validity Points Total

3 points

Clinical Validity Classification

Limited

Molecular Mechanism

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Curation Summary

LIMITED, not writting a summary at this time.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 08.23.2023,https://broadinstitute.atlassian.net/browse/BCL-168