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Background Williams (WS) and Down syndromes (DS) are two genetic disorders that involve intellectual disability (ID) and have been extensively studied over the past decades because of the unique linguistic profiles they exhibit. Recent investigations seek to explore the fractionation of linguistic components within the cognitive system using genetically based neurodevelopmental disorders such as WS and DS and to identify different profiles of linguistic function in these two groups of individuals. Method The ‘expressive vocabulary’, ‘receptive vocabulary’, ‘word opposites’ and ‘word definitions’ subtests (Level 1) of the Test of Word Knowledge (TOWK) were used to assess lexical skills in six children with WS and five children with DS. Results Our findings indicate that the two syndromes exhibit substantial differences on linguistic tasks with individuals with WS performing at a higher level compared to those with DS and producing atypical responses in word definitions. The pattern of errors for each syndrome is qualitatively different suggesting that their underlying linguistic mechanisms are distinctive even though ID is similar. Conclusions This study supports the differential outcome of two chromosomal disorders with similar ID. It also argues in favour of the large within group variability of the two syndromes that is not related to mental age but rather to different underlying mechanisms supporting language. These findings are discussed in the light of the current evidence concerning linguistic knowledge of neurodevelopmental and genetic disorders.