Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

联觉是一种罕见的非病理现象，一种感觉的刺激会自动激发另一种感觉的次级知觉。据推测，联觉者表现出非典型的结构和功能神经连接，这是由于发育过程中皮质布线的差异造成的，但潜在的分子机制尚不清楚。这种特征在患有自闭症谱系障碍和具有学者能力的人中似乎也更常见。先前的连锁研究在多个家族中寻找具有大效应的共享基因座，但取得的成功有限。为了解决候选基因严重缺乏的问题，我们对三个具有影响三代或三代以上多个亲属的声色（听觉-视觉）联觉的家庭应用了全外显子组测序。我们在每个家族中鉴定出了与联觉完全共分离的罕见遗传变异，发现了 37 个感兴趣的基因。与表明遗传异质性的报告一致，家庭之间没有共享变异。基因本体分析强调了六个基因——COL4A1 、 ITGA2 、 MYO10 、 ROBO3 、 SLC9A6和SLIT2——与轴突发生相关，并在儿童早期联觉关联形成时表达。这些结果与基于神经影像学的关于超连接在联觉病因学中的作用的假设一致，并为组织我们的感觉体验的神经生物学提供了一个潜在的切入点。