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Rare variants in axonogenesis genes connect three families with sound–color synesthesia
Edited by Edward M. Hubbard, University of Wisconsin–Madison, Madison, WI, and accepted by Editorial Board Member Randolph Blake January 23, 2018 (received for review September 5, 2017)

Significance
Our physical senses are separated not only into distinct experiences but also into specialized regions within the cerebral cortex. Synesthesia is a neurological phenomenon that causes unusual links between sensory experiences, and its molecular basis is completely unknown. We demonstrate that three families who experience color when listening to sounds are connected by rare genetic variants affecting genes that contribute to axonogenesis, a process essential for neuronal connections within and across brain regions. Multiple genes with similar activity patterns during neural development fall within parts of the genome previously linked to the condition. Our results connect synesthetes’ altered structural and functional connectivity to genes that support the development of those connections.
Abstract
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.
Footnotes
↵1S.B.-C. and S.E.F. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: simon.fisher{at}mpi.nl.
Author contributions: A.K.T., K.S.K., S.B.-C., and S.E.F. designed research; A.K.T., K.S.K., A.V., and J.E.A. performed research; A.K.T., K.S.K., A.V., and S.E.F. analyzed data; A.K.T. and S.E.F. wrote the paper; and J.E.A. and S.B.-C. collected synesthesia families.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. E.M.H. is a guest editor invited by the Editorial Board.
Data deposition: The datasets generated during the current study are available upon request from The Language Archive (TLA: https://corpus1.mpi.nl/ds/asv/?0), a public data archive hosted by the Max Planck Institute for Psycholinguistics. The data are stored under the node IDs MPI1758324# and MPI1815362# and are accessible at https://hdl.handle.net/1839/00-0000-0000-001A-8756-4@view.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1715492115/-/DCSupplemental.
- Copyright © 2018 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
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