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Synesthesia Family Exomes Lead to Rare Axon-Related Gene Variants

NEW YORK (GenomeWeb) – By focusing on several families with a form of synesthesia marked by color manifestations when listening to sounds, investigators in the Netherlands and the UK unearthed rare variants enriched in genes involved in the formation of the long axon fibers that transmit electrical signals away from neuron bodies.

As reported online yesterday in the Proceedings of the National Academy of Sciences, the team did exome sequencing to profile members of three multi-generation families affected with auditory-visual synesthesia that linked sounds to color. The search led to alterations in coding regions of more than three dozen genes, converging on half a dozen axonogenesis-associated genes, though the authors cautioned that pathways underlying other forms of synesthesia may differ from those discovered in the families profiled.

"This research is revealing how genetic variation can modify our sensory experiences, potentially via altered connectivity in the brain," co-senior author Simon Baron-Cohen, director of the University of Cambridge Autism Research Centre, said in a statement. "Synesthesia is a clear example of neurodiversity which we should respect and celebrate."

Synesthesia is a rare condition that involves unusual neurosensory connections in individuals who are often "neurotypical" overall, the team explained. 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.

"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," first author Amanda Tilot, a genetics researcher at the Max Planck Institute for Psycholinguistics, said in a statement. "We suspect some of the answers lie in people's genetic makeup."

To explore these pathways in one type of synesthesia, the researchers did 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 for the Simons Foundation's AutDB database.

And in the current analysis, the 37 rare variants tended to converge on six genes — COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2 — from axonogenesis and cell migration pathways.

Available gene- and protein expression data indicated that these genes are expressed in the human brain, particularly during development and childhood, while the researchers' 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.

"It remains to be seen if other forms of synesthesia will involve alterations in axon growth and guidance," the authors concluded. "This study focused on relatively rare genetic variation occurring in families with multiple generations of synesthetes; assessing potential roles of common variation represents an intriguing question for the future."