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.
Highlights
Dyslexia is a prevalent human neurodevelopmental condition, characterized by a difficulty learning to read despite conventional instruction, adequate educational opportunities and IQ, and a lack of sensory impairments (Shaywitz et al 1992)
We considered noncoding variants based on the FIRE (Functional Inference of Regulators of Expression) score (Ioannidis et al 2017), which is predictive of cis expression quantitative trait loci, but does not rely on conservation information as GWAVA and CADD do
We adopted a strategy of combining linkage analysis with whole-genome sequencing (WGS) to identify genetic variants that may contribute to dyslexia in a large three-generation family in which around half of the relatives are affected
Summary
Dyslexia is a prevalent human neurodevelopmental condition, characterized by a difficulty learning to read despite conventional instruction, adequate educational opportunities and IQ, and a lack of sensory impairments (Shaywitz et al 1992). It shows familial clustering and has been reported to be moderately heritable in a range of samples, with heritability estimates from 0.3 to 0.8 (Peterson and Pennington 2015). Multiple genetic variants are likely to act as risk factors contributing to the liability of dyslexia.
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