Lateralized nervous system function is phylogenetically old but fundamentally important for human brain function. Although altered in developmental and psychiatric disorders, we know little about its genetics. To understand the genetic origins of hemispheric specialization, we investigated laterality in a genetic disorder, Williams Syndrome (WS), caused by ~27 deleted genes on 7q11.2. Using a multidisciplinary approach combining individuals’ molecular genetic, electrophysiological, and behavioral data, we identify reversed lateralization, from right to left hemisphere for perceiving direction of motion in WS and show hemispheric strengths are inversely correlated. Moreover, we correlate decreased transcript levels of the deleted gene BUD23, with strength of the reversed lateralization and with decreased performance in mental rotation, another right hemisphere lateralized function. The results implicate dosed BUD23, an 18S ribosomal RNA methyltransferase, in human brain laterality, support an evolutionary origin and provide altered lateralization as a novel mechanism for impaired cognition in genetic and behavioral disorders.