Williams Syndrome: on the genetic basis of human cognition

Abstract

Williams syndrome (WMS) is a most compelling model of human cognition, of human genome organization and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurodevelopmental deficits. Given the striking peaks and valleys in neurocognition including deficits in visual-spatial and global processing, preserved language and face processing, hypersociability, and heightened affect, the goal of this work has been to identify the genes responsible. To do this, we have generated an integrated physical, genetic and transcriptional map of the WMS and flanking regions using multi-color metaphase and interphase FISH of BACs and PACs, BAC end sequencing, PCR gene marker and microsatellite, large scale sequencing, cDNA library and database analyses.

The results indicate the genomic organization of the WMS region as a complex of duplicated regions flanking a largely single copy region. There are at least two common deletion breakpoints, one in the centromeric and at least two in the telomeric repeated regions. Primate studies indicate an evolutionary hot-spot for chromosomal inversion in the WMS region. A cognitive phenotypic map of WMS has been generated that combines previous data with five further WMS subjects and atypical deletions; two larger (deleted for D7S489L) and three smaller, deleted for only subsets of genes. The results establish regions and consequent gene candidates for characteristic WMS features including visual-spatial defidits, global processing. The approach provides the basis for defining pathways linking genetic underpinnings with the neuroanatomical, functional and behavioural consequences that result in human cognition.