Turner syndrome (TS) is a human genetic disorder involving females who lack all or part of one X chromosome. Classic TS features include short stature, infertility, and anatomic abnormalities. More recently, characteristic neurocognitive deficits in nonverbal domains such as visual-spatial abilities have been recognized as part of the syndrome. Our original grant proposed to map loci responsible for specific TS cognitive and physical features by collecting a large number of subjects with heterogeneous X chromosome deletions, mapping the deletions using molecular methods, and thoroughly analyzing associated phenotypes. Rigorous statistical analysis showed that deletions of certain regions of the short arm of the X chromosome were associated with specific TS phenotypes, including neurocognitive deficits, short stature, and ovarian failure. Cognitive and physical aspects of the phenotype were dissociable. We narrowed the location of gene(s) responsible for a major component of the TS neurocognitive phenotype to an interval of the distal short arm (Xp) spanning only ~1% of the X chromosome. This same interval has been previously shown to contain a gene termed SHOX, deletions or mutations of which cause short stature and other TS skeletal abnormalities. Following the paradigm of Williams syndrome, another complex genetic disorder with characteristic physical and cognitive phenotypes, we reasoned that TS represents a genetic and phenotypic continuum associated with X chromosome deletions. Furthermore, physical phenotypes associated with SHOX deletions could be used to ascertain a population of subjects with small distal Xp deletions in and around the TS neurocognitive critical region without bias with regard to their neurocognitive phenotypes. Fine-mapping these subjects' deletions will allow us to narrow the TS neurocognitive critical region to a specific gene(s). Furthermore, characterizing the neurocognitive profile of subjects with SHOX point mutations or distal Xp deletions limited just to SHOX will allow us to critically test whether this known TS gene also plays a role in the neurocognitive phenotype. The proposed study takes advantage of our existing clinical collaborations as well as large referral populations for SHOX-associated disorders in Dallas and Philadelphia to obtain a sufficient sample size of unrelated distal Xp deletion subjects for rigorous statistical analyses. The project will combine molecular characterization of subjects with detailed cognitive evaluations to elucidate the role of SHOX or other pseudoautosomal gene deficiencies in the TS neurocognitive phenotype.
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