Synaesthesia is a rare neurodevelopmental non-disease condition estimated to affect <2% of the human population. People with synaesthesia experience cross-modal perceptions, such as visual images triggered by sounds, words that elicit tastes, or involuntary and stable associations of letters and/or numbers with colours. It has been hypothesized that synaesthesia is a consequence of relative hyperconnectivity in the brain. The well-documented familial clustering of synaesthesia suggests that genes play a significant role. However, results of previous linkage studies indicate that synaesthesia is likely to be genetically heterogeneous; thus, a similar phenotype may result from different combinations of contributing genes and their alleles in different cases. In the current study, we used next-generation sequencing to investigate families in which multiple relatives have synaesthesia. We sequenced exomes of people with and without synaesthesia in three such families (13 synaesthetes and 4 non-synaesthetes in total), to detect rare genetic variants that segregate with the trait. We thereby identified 77 rare (MAF<0.05) nonsynonymous protein-coding variants that segregate with the phenotype in those families. Of the 77 variants, 10 were located within previously reported suggestive linkage regions on chromosomes 2q13 and 4q28.3. Future investigations will use data from gene expression and protein function in cells and tissues to determine which of these candidate variants are most likely to have roles in aetiology. Furthermore, common variation in the same candidate genes can be tested for association in independent case-control datasets, to complement the family-based studies described here. Identification of genes implicated in synaesthesia will not only shed light on how this intriguing trait arises, but also promises novel insight into the molecular bases of neural connectivity in the human developing brain.