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 30CGG 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.
