Dyslexia is a specific difficulty in learning to read that affects 5-10% of school-aged children and is strongly influenced by genetic factors. While previous studies have identified common genetic variants associated with dyslexia, the role of rare variants has only recently begun to emerge from pedigree studies and has yet to be systematically tested in larger cohorts. Here, we present a whole-exome sequencing (WES) study of 53 individuals with dyslexia, followed by replication analysis in 38 cases with reading difficulties and 82 controls assessed with reading measures. Our stringent bioinformatics filtering strategy highlighted five brain-expressed genes carrying rare variants: CACNA1D, CACNA1G, CLDN3, CNGB1, and CP. Notably, a specific variant (7-73769649-G-A) in the CLDN3 gene was identified in six independent cases, showing a four-fold higher frequency compared to population reference datasets. CACNA1D and CACNA1G encode subunits of voltage-gated calcium channels (VGCC) expressed in neurons, and variants in both genes have been implicated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and epilepsy. Segregation analysis in available family members were consistent with patterns of dominant inheritance with variable expressivity. In total, high-impact variants in the five genes of interest were found in 26% (N = 14) of individuals of the discovery cohort. Overall, our findings support the involvement of rare variants in developmental dyslexia and indicate that larger WES studies may uncover additional associated genes.

The authors have declared no competing interest.

Medical Research Scotland [PhD-50010-2019]; Action Medical Research Action/The Chief Scientist Office (CSO), Scotland grant [GN2614]; The Royal Society [UF100463]. Bioinformatic analysis was conducted on the UK's Crop Diversity Bioinformatics HPC which is funded by the BBSRC [BB/S019669/1]. The recruitment of the Discovery cohort was supported by Wellcome Trust Grants [076566/Z/05/Z and 075491/Z/04] and a Waterloo Foundation Grant [797 1720]. Recruitment and analysis of the Replication cohorts was supported by Wellcome Trust Programme Grants [082498], and European Research Council Advanced Grant [694189].

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Oxfordshire Psychiatric Research Ethics Committee, Aston University Ethics Committee and the Berkshire NHS Research Ethics Committee gave ethical approval for this study

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