GENETICS OF COGNITION IN ADULT TURNER SYNDROME

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DESCRIPTION (adapted from applicant's abstract): Turner syndrome (TS) is the human genetic disorder involving females who lack all or part of one X chromosome. The complex phenotype includes ovarian failure, a characteristic neurocognitive profile, and typical physical features. TS features are associated not only with complete monosomy X but also with partial deletions of either the short (Xp) or long (Xq) arm (partial monosomy X). Impaired visual-spatial/perceptual abilities are characteristic of TS children and adults of varying races and socioeconomic status, but global developmental delay is uncommon. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities, hormonal deficiencies, and other unspecified determinants of cognitive ability. Furthermore, an additional genetic mechanism, imprinting, may contribute to cognitive deficits associated with monosomy X. The investigators propose in the current study to delineate the genetic factors that account for the Turner syndrome neurocognitive phenotype in adults by 1) mapping the TS-associated neurocognitive phenotypes in partial monosomy X women, 2) collecting parent-of-origin data from adult Turner syndrome subjects for imprinting studies, and 3) contrasting women who have both genetic (X chromosome) and hormonal abnormalities with women who have only a hormonal abnormality (idiopathic premature ovarian failure). These studies will test the hypothesis from preliminary data that cognitive dysfunction associated with monosomy X maps to distal Xp. As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic factors that influence female cognitive development. There is potentially informative genetic and phenotypic variation among TS subjects with partial X deletions. Careful clinical and molecular characterization of these unusual subjects, who represent "experiments in nature," could link the TS phenotype of impaired visual spatial/perceptual ability to specific X chromosome regions. Turner syndrome is an excellent model for such phenotype mapping studies because of its prevalence, the well-characterized phenotype, and the wealth of molecular resources available for the X chromosome. Phenotype mapping of X deletions will be helpful for genetic counseling. Characterization of specific TS causative genes would provide insight into the pathophysiology of 45,X, Turner syndrome, as well as the process of normal neurocognitive development.