Distribution of the HTT Gene A1 and A2 Haplotypes Worldwide: A Systematic Review

Huntington's disease (HD)(MIM:143100) is an severe autosomal dominant neurodegenerative disease caused by the dynamic expansion of CAG trinucleotides (> 35) in the HTT gene [Genomic Coordinates- (GRCh38):4:3,074,680-3,243,959].

The aim of this systematic review was to investigate the reported associations between the frequencies of the A1 and A2 haplotypes in HD-affected and non-affected populations from different countries on different continents, in order to demonstrate the overall profile of these haplotypes worldwide, pointing towards the most frequent haplotypes that could be useful for HTT mutant-specific allele silencing in different populations.

Publications in MEDLINE (PubMed) and Embase from the last 10 years (PROSPERO CRD42018115282) were assessed.

A total of 20 articles from 113 were selected for evaluation in their entirety, and eight were eligible for this study.

Regardless of the size of the CAG tract, the articles included in this review demonstrate that populations with high HD prevalence present higher frequencies of the A1 or A2 haplotypes than populations exhibiting low HD prevalence, even when similar average CAG numbers are noted. Based on the presented articles, we suggest that the haplotypic profile is more closely related to the ancestral origin than to the size of the CAG tract. The identification of populations presenting a higher frequency of high-risk genotypes can contribute to more accurate genetic counseling, in addition to providing knowledge on HD epidemiology. According to the continued progress in the development of specific genetic silencing therapies by different research groups and pharmaceutical companies, such as haplotype targeting strategies for allele-specific HTT suppression, we conclude that the definition of haplotypes in phase with CAG expansions will contribute to the design of gene-silencing drugs specific for different populations worldwide.