Synesthesia Family Exomes Lead to Rare Gene Variants

Synesthesia is a neurological phenomenon that causes unusual links between sensory experiences, and its molecular basis is completely unknown. Synesthesia is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to automatic, involuntary experiences in a second sensory or cognitive pathway.

In many cases, color sensations are triggered by specific cues such as the sight of letters, numbers, or words, though other sensory stimuli and secondary perceptions may be linked. While past studies hinted that enhanced brain neuronal connectivity contributes to such processes, the genetic basis of these interconnections remains murkier.


An international team of scientists led by those at the Max Planck Institute for Psycholinguistics (Nijmegen, The Netherlands) identified three multi-generation families affected with auditory-visual synesthesia that linked sounds to color. To explore these pathways in one type of synesthesia, the team performed whole-exome sequencing on several affected and unaffected family members in three auditory-visual synesthesia-affected pedigrees spanning at least three generations. From nearly 11,600 suspicious variants in the families, they narrowed in on 3,864 rare variants for additional analyses.

The team further focused in on 37 rare, heterozygous mutations that tracked with synesthesia in the families and followed a dominant inheritance pattern. Although the same variants were not found across families, three of the variants were previously linked to synesthesia in autism spectrum disorder-affected families profiled. DNA was extracted from blood, buccal swabs, or Oragene kits of 18 individuals from the three selected synesthesia families. Library preparation began with 3 μg of purified DNA. Enrichment for exonic regions was performed using the SOLiD-optimized Sure Select All Human Exon Kit followed by sequencing on 5500XL Genetic Analysis System.

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. Available gene- and protein expression data indicated that these genes are expressed in the human brain, particularly during development and childhood, while the investigator’s own array-based tests on six post-mortem brain samples supported the notion that the genes are expressed in parts of the brain previously implicated in synesthesia.

Amanda Katherine Tilot, PhD, the lead author of the study, said, “Brain imaging of adults with synesthesia suggests that their circuits are wired a little differently compared to people who don't make these extra sensory associations. What we don't know yet is how these differences develop. We suspect some of the answers lie in people's genetic makeup.” The study was published on March 5, 2018 in the journal Proceedings of the National Academy of Sciences.

Related Links:
Max Planck Institute for Psycholinguistics