Huntington’s disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world’s second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele’s read peak and the slippage ratio of the allele’s read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.

Background and objectives: The premanifest phase of Huntington’s disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed using artificial intelligence (AI) software in premanifest HD individuals, focusing on the relationship between CAG triplet expansion and structural biomarkers. Methods: The study included 36 individuals descending from families affected by HD in the Department of Atlántico. Sociodemographic data were collected, followed by peripheral blood sampling to extract genomic DNA for quantifying CAG trinucleotide repeats in the Huntingtin gene. Brain volumes were evaluated using AI software (Entelai/IMEXHS, v4.3.4) based on MRI volumetric images. Correlations between brain volumes and variables such as age, sex, and disease status were determined. All analyses were conducted using SPSS (v. IBM SPSS Statistics 26), with significance set at p < 0.05. Results: The analysis of brain volumes according to CAG repeat expansion shows that individuals with ≥40 repeats evidence significant increases in cerebrospinal fluid (CSF) volume and subcortical structures such as the amygdalae and left caudate nucleus, along with marked reductions in cerebral white matter, the cerebellum, brainstem, and left pallidum. In contrast, those with <40 repeats show minimal or moderate volumetric changes, primarily in white matter and CSF. Conclusions: These findings suggest that CAG expansion selectively impacts key brain regions, potentially influencing the progression of Huntington’s disease, and that AI in neuroimaging could identify structural biomarkers long before clinical symptoms appear.

Background The second world's most extensive cluster of patients affected with Huntington’s disease (HD), a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene, inhabits Juan de Acosta, a city located on the Caribbean coast of Colombia. This group represents the second most extensive pedigree clustering HD in the world. Methods We included 291 descendants of families living in Juan de Acosta, Colombia, who had at least one member with HD. Blood samples were obtained, and genomic DNA was extracted. The HTT CAG expansion was quantified using an amplicon sequencing protocol. Statistical and bioinformatic analyses were conducted using several modules implemented in R. Statistical threshold significance was set at P < 0.05. Results A total of 33 HD patients were analyzed, and a mean of 21.91 HTT CAG repeats with a standard deviation of 8.92 copies was obtained. The most affected individuals were adults, and the most common primary and secondary alleles were 17/7 and 17/10, respectively. Mosaicism increased with age in participants with HD, and slippage analyses revealed differences by HD allele type for the secondary allele, but no significant differences were observed by sex. Slippage tended to increase with the number of CAG repeats in participants with HD, but the increase was not statistically significant. The most common haplotype was 17/7_17/10. Conclusion This study analyzed the genetic and molecular features of HD by examining 291 participants, including 33 with HD. Mosaicism was found to increase with age in subjects with HD, particularly for the secondary allele; the most common haplotype was 17/7_17/10. Slippage for the secondary allele varied by HD allele type, but no significant difference in slippage was observed by sex. The findings offer valuable insights into the disease and could have implications for future research and clinical management.