KLINEFELTERS-SYNDROME AS A MODEL OF ANOMALOUS CEREBRAL LATERALITY - TESTING GENE DOSAGE IN THE X-CHROMOSOME PSEUDOAUTOSOMAL REGION USING A DNA MICROARRAY

Consistent handedness and language laterality are two of the most stri king behavioral and cognitive asymmetries observed in humans. Alterati ons in the typical pattern of cerebral laterality, termed ''anomalous dominance,'' is observed in left-handers and some patients with verbal learning disabilities. We undercook the study of a genetically distin ct group of subjects, XXY males (Klinefelter's syndrome; KS), who demo nstrate anomalous dominance in a variety of testing paradigms in order to begin to elucidate the molecular basis of anomalous dominance in t his population. KS subjects manifest specific verbal learning disabili ty, evidence of altered functional laterality for phonologic processin g, and an increase in left-handedness when measured by skill. It is pr oposed that an alteration in gene dosage in the pseudoautosomal region (PAR) of the sex chromosomes is the most likely explanation For anoma lous dominance in these patients. This is especially intriguing in lig ht of previously described genetic models of cerebral laterality that suggest a contributing locus in the PAR, or adjacent high homology reg ions of the X chromosome. We have developed an ordered DNA micro array covering the X chromosome PAR at high resolution for hybridization wi th two-color fluorescently labeled probes. We demonstrate the ability to detect changes in hybridization signal that will facilicate efficie nt large-scale screening of this region for alterations in gene dosage associated with features of anomalous dominance and other cognitive o r behavioral phenotypes. (C) 1998 Wiley-Liss, Inc.