Project: Research project

Project Details


The fragile X syndrome is the most common familial cause of mental
retardation known. Although males are most significantly affected, females
are also affected and there is a broad range of variability in the
physical, neurocognitive and emotional phenotype. Some of the factors
which affect this variation in penetrance for the heterozygote include her
position in the pedigree, percent fragility and X-inactivation. The
overall goals of the proposed research are to better define the physical,
neurocognitive and emotional/social phenotype of the fragile X
heterozygote, to examine the relationships among these phenotype domains
and to test different genetic and environmental explanations for the range
of phenotypic expression. One promising genetic hypothesis is Laird's
(1987) imprinting theory which makes specific, but as yet untested
predictions about phenotypic expression in imprinted vs. nonimprinted
heterozygotes. To accomplish these goals, we will study three groups of fragile X
heterozygotes between the ages of 16 to 45 and with an IQ of 65 or higher:
1) those who do not express the fragile X chromosome but are obligate
carriers or DNA probe positive for the gene (nonimprinted), 2) those who
express the fragile X gene in >2 but 10%
of their cells (imprinted females). To evaluate environmental sources of
phenotype variance, we will utilize nonfragile X control females who have
experienced the stressor of either up in a fragile X family or raising a
developmentally delayed child. An extensive evaluation in three domains will occur: 1) In the
physical/historical domain, a history of medical, school and behavioral
problems will be obtained. A physical exam will also document features
which are associated with the fragile X syndrome, 2) In the neurocognitive
domain, an assessment of frontal lobe functions, social cognition, right
hemisphere functions, left hemisphere functions, general intelligence, and
academic skills will be done. These evaluations will assess competing
hypotheses regarding a specific neurocognitive phenotype in heterozygotes.
3) In the emotional domain, psychopathology, environmental stressors and
coping skills will be assessed by a structured interview, direct evaluation
and the completion of checklists. These evaluations will also allow us to test several predictions of Laird's
imprinting hypothesis, including a lack of involvement of unimprinted
heterozygotes (who are fragile X negative or daughters of nonpenetrant
males), and the variable influences of X-inactivation on cognitive
abilities of imprinted vs. nonimprinted heterozygotes. The study of
fragile X-heterozygotes provides a unique opportunity to study the effects
of a fairly common X chromosome locus on psychopathology and to advance our
understanding of the relationship between neurocognitive problems and
emotional dysfunction.
Effective start/end date12/1/897/31/96


  • National Institutes of Health: $266,563.00
  • National Institutes of Health: $257,181.00


  • Medicine(all)


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.