ENJournal of Huntington's Disease | Clinical Phenotype of Carriers of Intermediate Alleles in the HTT Gene: A Scoping Review
日期: February 03, 2026
分类: Frontiers
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This study systematically reviews the clinical characteristics of carriers of intermediate alleles (27–35 CAG) in the HTT gene and finds significant bias in the existing literature, making it impossible to establish a definitive association with specific clinical phenotypes.
Literature Overview
The article titled 'The clinical phenotype of carriers of intermediate alleles in the huntingtin gene: A scoping review,' published in the Journal of Huntington's Disease, reviews and summarizes the existing literature on the clinical phenotypes of individuals carrying intermediate alleles (IAs, 27–35 CAG repeats) in the HTT gene. By systematically searching peer-reviewed articles published between 1993 and July 2024 in Embase, PubMed, and Web of Science, the study included 51 articles for analysis. The results show that although some IA carriers report motor, cognitive, or psychiatric symptoms and neuroimaging abnormalities, these manifestations are non-specific and subject to significant publication and selection bias. Therefore, there is currently insufficient evidence to establish a causal relationship between intermediate alleles and specific clinical phenotypes. The article emphasizes that future research should involve detailed phenotypic recording in larger cohorts matched with healthy controls to improve evidence quality.Background Knowledge
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder caused by abnormal CAG trinucleotide repeat expansion in the HTT gene located on the short arm of chromosome 4. Typical HD patients have ≥36 CAG repeats, with 36–39 considered the reduced penetrance range. Healthy individuals typically carry 6–35 repeats, while 27–35 repeats define intermediate alleles (IAs). Although IAs are not pathogenic, they exhibit germline instability and may expand into the disease-causing range across generations. While IAs are not considered a direct cause of HD, clinical cases have been reported in which carriers of IAs exhibit HD-like symptoms (e.g., chorea, cognitive decline, depression). However, it remains inconclusive whether these symptoms are driven by IAs. Current research focuses on the relationship between CAG repeat length and age of onset, somatic CAG instability, and the impact of loss of interrupting sequences (e.g., CAA) on pathogenicity. Challenges include the unclear clinical significance of IAs, lack of large-scale prospective studies, and substantial publication bias—symptomatic individuals are more likely to be reported. Additionally, differences in diagnostic pathways introduce selection bias: individuals with a family history are often tested during asymptomatic phases, while sporadic cases are tested due to symptoms, leading to overestimation of the association between IAs and phenotypes. This study uses a scoping review approach to systematically map the existing evidence to determine whether IAs are associated with specific clinical phenotypes, providing a basis for genetic counseling and mechanistic research.
Methods and Experiments
This study followed the PRISMA-ScR guidelines for a scoping review, systematically searching relevant literature published from 1993 to July 2024 in Embase, PubMed, and Web of Science. Inclusion criteria were: human subjects; information on intermediate alleles in the HTT gene (27–35 CAG repeats); and reporting of neurological clinical outcomes. Exclusion criteria included reviews, conference abstracts, non-English/Dutch articles, and papers focusing solely on genetic counseling or intergenerational instability. Two researchers independently screened titles and abstracts, followed by full-text review. Data extraction included demographic information, CAG repeat length, symptom types, family history, medication use, and neuroimaging results. Symptoms were categorized as motor, cognitive, and neuropsychiatric, and standardized using the PBA-s scale. Cohort studies and case reports were analyzed separately, with linear regression used to assess the relationship between CAG repeat length and age at symptom onset.Key Findings and Insights
Implications and Future Directions
The study reveals limited evidence quality regarding the clinical significance of intermediate alleles in the HTT gene, primarily due to bias and data gaps in the literature. The findings suggest clinicians should exercise caution when attributing neurological symptoms in IA carriers and should rule out other potential causes. The study emphasizes the need for prospective, multicenter cohort studies to systematically collect detailed clinical, imaging, and biomarker data from IA carriers and compare them with age- and sex-matched healthy controls to clarify their natural history.
Additionally, molecular mechanisms such as somatic CAG instability and loss of CAA interrupting sequences should be explored for their roles in IA phenotypic expression. Developing more precise detection methods to identify these variants will help clarify their pathogenic potential. This study provides important guidance for genetic counseling: IA should not be interpreted as an explanation for HD symptoms unless alternative diagnoses are ruled out.
Conclusion
This study systematically reviewed existing literature to evaluate the clinical phenotype characteristics of carriers of intermediate alleles (CAG 27–35) in the HTT gene. Although some case reports describe movement disorders, cognitive decline, and psychiatric symptoms, and neuroimaging reveals abnormalities such as brain atrophy, these manifestations are common in the elderly and lack specificity. More importantly, the analysis reveals significant publication and selection bias—symptomatic individuals are more likely to be reported, while asymptomatic carriers are often classified as controls, leading to overestimation of the association between IAs and symptoms. Overall, cohort studies do not show significant clinical differences between IA carriers and healthy controls. Therefore, current evidence is insufficient to support that intermediate alleles directly cause Huntington’s disease-like phenotypes. Future research should adopt large-sample, prospective designs combined with molecular mechanism analyses to clarify the true clinical significance of IAs. This conclusion provides important guidance for genetic counseling and clinical diagnosis, reminding physicians to comprehensively evaluate genetic test results and avoid over-attribution.
