Research

A Turner syndrome neurocognitive phenotype maps to Xp22.3

Andrew R Zinn¹ , David Roeltgen² , Gerry Stefanatos³ , Purita Ramos¹ , Frederick F Elder⁴ , Harvey Kushner⁵ , Karen Kowal⁶ and Judith L Ross⁶

¹  Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School, Dallas TX, USA

²  Cooper University Hospital, Robert Wood Johnson Medical School, Camden, NJ, USA

³  MossRehab Research Institute, Albert Einstein Medical Center, Thomas Jefferson University, Philadelphia, PA,

⁴  Department of Pathology, The University of Texas Southwestern Medical School, Dallas TX 75390, USA

⁵  Biomedical Computer Research Institute, Philadelphia, PA, USA

⁶  Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA

author email corresponding author email

Behavioral and Brain Functions 2007, 3:24doi:10.1186/1744-9081-3-24

Published:	21 May 2007

Abstract

Background

Turner 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.

Methods

Subjects 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.

Results

We 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.

Conclusion

Detailed 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.