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Factors Associated with HD CAG repeat instability in Huntington’s disease
  1. Vanessa Wheeler (wheeler{at}helix.mgh.harvard.edu)
  1. Massachusetts General Hospital, United States
    1. Francesca Persichetti (persiche{at}sissa.it)
    1. International School for Advanced Studies, Italy
      1. Sandra McNeil
      1. Massachusetts General Hospital, United States
        1. Jayalakshmi Mysore (mysore{at}chgr.mgh.harvard.edu)
        1. Massachusetts General Hospital, United States
          1. Sony Mysore (sony.mysore{at}gmail.com)
          1. Massachusetts General Hospital, United States
            1. Marcy MacDonald (macdonam{at}helix.mgh.harvard.edu)
            1. Massachusetts General Hospital, United States
              1. Richard Myers (rmyers{at}bu.edu)
              1. Boston University, United States
                1. James Gusella (gusella{at}helix.mgh.harvard.edu)
                1. Massachusetts General Hospital, United States
                  1. Nancy Wexler (wexlern{at}pi.cpmc.columbia.edu)
                  1. Columbia University, United States
                    1. The U.S-Venezuela Collaborative Research Group Wexler
                    1. Columbia University, United States

                      Abstract

                      <strong>Background:</strong> The Huntington's disease (HD) CAG repeat exhibits dramatic instability upon transmission to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of HD gene carriers. <br /><strong>Objective:</strong> To investigate the factors associated with intergenerational HD CAG repeat instability <br /><strong>Methods:</strong> We investigated HD CAG repeat variability in a collection of 112 sperm DNAs from HD gene positive males of a large Venezuelan cohort and transmission instability for 184 father-offspring and 311 mother-offspring pairs from this pedigree. <br /><strong>Results:</strong> We confirm previous observations that CAG repeat length is the strongest predictor of repeat length variability in sperm, but do not find any correlation between CAG repeat instability and either age at the time of sperm donation or affection status. Repeat length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring. Significant sib-sib correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability. <br /><strong>Conclusions:</strong> Although CAG repeat length is the main contributor to intergenerational instability, genetic factors may play a modifying role.

                      • CAG repeat instability
                      • Huntington's disease
                      • genetic factors
                      • spermatogenesis

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