# The clinical phenotype of carriers of intermediate alleles in the huntingtin gene: A scoping review

## TL;DR

This review examines whether people with intermediate CAG repeats in the HTT gene show symptoms related to Huntington's disease, finding inconsistent and non-specific evidence.

## Contribution

The study provides a comprehensive scoping review of clinical phenotypes in intermediate allele carriers of the HTT gene.

## Key findings

- Case reports show 90% of intermediate allele carriers had symptoms or neuroimaging abnormalities.
- Cohort studies found limited significant differences between intermediate allele carriers and controls.
- The evidence is insufficient to define a clear clinical phenotype due to poor data quality and publication bias.

## Abstract

Huntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin (HTT) gene. Intermediate alleles (IAs, CAG = 27–35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature.

To review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers.

Peer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included.

In case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls.

Based on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.