Persons with trisomy 21 (T21) and Williams-Beuren syndrome (WBS) have different brain abnormalities which may affect manual laterality. We assessed 45 persons with T21 and 34 with WBS (mean age 13) and 81 typically developing children (TD). Manual laterality was assessed with a fifteen-item task administered two times, and Bishop's card-reaching task. We found more left-handers in the T21 group compared to the other two groups. Inconsistent laterality was higher in the two groups with genetic diseases than in the TD group. For Bishop's test, both T21 and WBS participants were less right-oriented than the TD group. They displayed different response patterns in midline crossing when reaching for the cards, but did not display more midline crossing inhibition than the TD group. Is atypical handedness linked to specific genetic syndromes and, more specifically for persons with T21, to the trisomy of some of the genes?