Genotype-Phenotype Study with Huntington’s Disease Postmortem Brains

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington gene (HTT), affecting approximately 1 in 5000–10,000 individuals worldwide. This disorder is characterized by progressive motor dysfunction, cognitive decline, and behavioral changes, with adult-onset typically occurring between the ages of 35 and 55. Early loss of medium spiny neurons in the caudate and putamen is a hallmark of the disease. The objective of this study was to investigate the genetic modifiers of HD by analyzing postmortem HD brain samples through genotyping, to assess their potential relevance in the molecular pathology of the disease. Methods involved extracting genomic DNA from postmortem brain tissue, followed by PCR amplification and sequencing using ABI sequencing, the Light Cycler, and Miseq platforms. Genotyping included HD CAG repeats and associated SNPs, as well as assays for HD modifiers. 

Results indicated that all brain samples contained expanded CAG repeats, with the repeat length correlating to both the stage of disease and the age of diagnosis. A higher percentage of juvenile-onset cases were observed in our cohort, with CAG repeat length correlating to age of onset and death. MiSeq data confirmed the CAG repeat lengths for 29 of 31 normal alleles and 26 expanded alleles. Notably, 24 brains exhibited modifier SNP alleles, including variants influencing disease progression. Our overarching conclusions were that successful genotyping revealed strong correlations between HTT CAG repeat length and both age of onset and death, while the identification of modifier alleles may provide valuable insights into disease variability. These findings underscore the significance of genetic modifiers in HD progression and highlight potential avenues for future therapeutic targets.

For more information: emhenderson@eckerd.edu 

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