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

Amaia Carrion-Castillo, Sara B. Estruch, Ben Maassen, Barbara Franke, Clyde Francks, Simon E Fisher*

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    2 Citaten (Scopus)
    36 Downloads (Pure)

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    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.

    Originele taal-2English
    Pagina's (van-tot)1183-1200
    Aantal pagina's18
    TijdschriftHUMAN GENETICS
    Volume140
    Nummer van het tijdschrift8
    Vroegere onlinedatum2-jun-2021
    DOI's
    StatusPublished - aug-2021

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