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

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.

Linkage and next generation sequencing (NGS) data in six large Danish families with dyslexia

“…For all ve loci we can nd support in the literature either as linkage analysis, association studies or CNV mapping. The combination of linkage analyses of large families and the use of NGS of the mapped regions is relatively new 21,22 . The lack of deleterious mutation in coding genes causing DD suggest mutations for DD must involve regulation of genes involved in neurological processes.…”

“…The combination of whole genome linkage (WGL) analyses in large families and WGS of the linkage regions has resulted in novel DD candidate genes. Examples are an intron variant with cis-regulatory effect on SEMA3C 21 and a missense variant in the gene SPY 22 . We have used a similar approach of WGL analyses of six large Danish DD families and analysed the linkage regions by WGS.…”

Hydrocephalus and Growth Retardation: A Fetal RNU4ATAC-opathy Missed by Whole-Exome Sequencing

“…The noncoding genes are mostly composed of regulatory elements that control gene expression. There is a growing body of literature indicating that variants in the noncoding genome are associated with congenital anomalies [Scacheri and Scacheri, 2015;Zhang and Lupski, 2015;Carrion-Castillo et al, 2021].…”

Human‐specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders

“…RD candidate genes and variants identified from family studies were collated mainly from the comprehensive review by Graham and Fisher 1 in addition to a few studies published after the review 15 , 30 , 31 (Data S1 ). A total of 42 genome‐wide significant associations were collected as population candidate genes and variants identified from the GWAS of RD 10 (Data S2 ).…”

“…Functional studies of some familial variants identified from family studies have provided some key insights into genetic regulation of RD. 1 , 15 However, such familial variants tend to be rare and thus are difficult to replicate in populations. 1 , 5 On the other hand, advances in uncovering genomic changes evolutionarily specific to humans have resulted in a rich source of human‐specific genomic information 16 , 17 , 18 that can also be used to derive novel insights from the candidate variants into diseases of interest.…”