Submission Details

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.