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  Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family

Carrion Castillo, A., Estruch, S. B., Maassen, B., Franke, B., Francks, C., & Fisher, S. E. (2021). Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family. Human Genetics, 140, 1183-1200. doi:10.1007/s00439-021-02289-w.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0008-A0B1-A Version Permalink: https://hdl.handle.net/21.11116/0000-0008-D6D4-7
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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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 Creators:
Carrion Castillo, Amaia1, 2, Author           
Estruch, Sara Busquets1, Author           
Maassen, Ben3, 4, Author
Franke, Barbara5, 6, Author
Francks, Clyde1, 6, 7, Author           
Fisher, Simon E.1, 6, Author           
Affiliations:
1Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, Nijmegen, NL, ou_792549              
2Basque Center on Cognition, Brain and Language, San Sebastian, Spain, ou_persistent22              
3University of Groningen, Groningen, The Netherlands, ou_persistent22              
4University Medical Center Groningen, Groningen, The Netherlands, ou_persistent22              
5Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
6Donders Institute for Brain, Cognition and Behaviour, External Organizations, ou_55236              
7Imaging Genomics, MPI for Psycholinguistics, Max Planck Society, ou_2579692              

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 Abstract: Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.

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Language(s): eng - English
 Dates: 2021-042021-06-022021-07
 Publication Status: Issued
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s00439-021-02289-w
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Title: Human Genetics
Source Genre: Journal
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Pages: - Volume / Issue: 140 Sequence Number: - Start / End Page: 1183 - 1200 Identifier: ISSN: 0340-6717
CoNE: https://pure.mpg.de/cone/journals/resource/954925519623