Abstract
BackgroundTurner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions.MethodsSubjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization.ResultsWe report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subject's age, were unrelated to the TSCS score.ConclusionDetailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.
Highlights
Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities
Comparison groups included adult women with 45, X TS and normal female adult controls. These were mostly the same subjects used in the construction and testing of the Turner Syndrome Cognitive Summary (TSCS) score, which was described above
To determine if SHOX might influence cognition, we evaluated the relationship between stature, deletion of SHOX, and TSCS score
Summary
Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. Girls and women with 45, X TS commonly demonstrate deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function and attentional abilities when compared to normal females matched for age, height, IQ, and socioeconomic status [2,3,4,5,6,7,8,9] Both hormonal and genetic factors may influence the cognitive development of TS females. Many of the cognitive deficits characteristic of TS are consistent across a wide age range, including children as well as estrogen-replaced adults [4,11,12] These deficits are generally not seen in females with premature ovarian failure and intact X chromosomes [13,14], suggesting a predominant role of genetic factors in the etiology of TS cognitive deficits
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