Origin of Fragile-X Syndrome through slipped-mispair recombination


    In the F1 generation, a man hemizygous for an X-chromosome with a 40-fold CGG repeat marries a woman heterozygous for X-chromosomes with 10- and 30-fold CGG repeats. Their daughter inherits the 40 CGG repeat from her father, and the 30 CGG repeat from her mother. In her germline, slipped-mispair recombination results in production of eggs with 10- or 60-fold CGG repeats. Because the event occurs only in her germline and not in the somatic tissues, she does not show the syndrome, even though the threshold for expression of Fragile-X syndrome is ~55CGG repeats

    In the F2 generation, the daughter marries a man with a 20-fold CGG repeat. One-half of their sons will inherit the 60 CGG chromosome and will likely show Fragile-X syndrome, and one-half of their daughters will be carriers.  Further slippage of the repeat region may occur in the F3 daughters' germlines. These daughters may or may not show the syndrome themselves: the phenotype is sex-influenced, with higher penetrance in males (80%) than females (30%), which may be due the presence of a 'standard' X-chromosome in heterozygous females.


All text material 2013 by Steven M. Carr