Molecular Genetics of Dyslexia: An Overview

Abstract

Dyslexia is a highly heritable learning disorder with a complex underlying genetic architecture. Over the past decade, researchers have pinpointed a number of candidate genes that may contribute to dyslexia susceptibility. Here, we provide an overview of the state of the art, describing how studies have moved from mapping potential risk loci, through identification of associated gene variants, to characterization of gene function in cellular and animal model systems. Work thus far has highlighted some intriguing mechanistic pathways, such as neuronal migration, axon guidance, and ciliary biology, but it is clear that we still have much to learn about the molecular networks that are involved. We end the review by highlighting the past, present, and future contributions of the Dutch Dyslexia Programme to studies of genetic factors. In particular, we emphasize the importance of relating genetic information to intermediate neurobiological measures, as well as the value of incorporating longitudinal and developmental data into molecular designs.

Distinguishing cause from effect – many deficits associated with developmental dyslexia may be a consequence of reduced and suboptimal reading experience

“…Twin studies estimate the heritability of the disorder to be between 0.50 and 0.60 (e.g. Grigorenko, 2001; see also Carrion-Castillo, Franke, & Fisher, 2013;Carrion-Castillo et al, 2017;Ramus, 2013). It has also been convincingly demonstrated that environmental factors, in particular SES, play a large role in reading skills (Bowey, 1995;Fluss et al, 2009).…”

Insights into the Genetic Foundations of Human Communication

“…Requires intensive follow-up studies to pinpoint etiological variants in regions of linkage. (Fisher and DeFries 2002) However it can sometimes be preferable to use quantitative measures to characterize affected individuals and their unaffected relatives, with the potential to also apply these across different related disorders, and even in unselected population cohorts (Carrion-Castillo et al 2013;Newbury et al 2014;Paracchini 2011). Quantitative measures circumvent problems arising from variations in diagnostic criteria.…”

“…A large number of subsequent studies have tested these candidate genes for association with affection status or with various psychometric measures, in cohorts with the same disorder as the original linkage cohort, or with the other of the two disorders (Carrion-Castillo et al 2013). Association with quantitative measures in general population cohorts has also been investigated (Paracchini et al 2008Scerri et al 2011).…”

“…Results have been mixed, with some studies reporting evidence of association while others do not. This outcome may partly be due to the arbitrary threshold of statistical significance applied in the studies, as well as difficulties in correcting for multiple testing, and it is possible that a subset of the original findings first implicating these candidates represent false-positives (Carrion-Castillo et al 2013;Newbury et al 2014). It is also debatable whether a finding of association with a different phenotype, or with the opposite direction of effect, represents a replication .…”

“…Research examining the basic biology of these proteins has led to some interesting discoveries. For example, DYX1C1 has been shown to play a role in the primary cilium and mutations of this gene are now known to cause a monogenic form of the disorder primary ciliary dyskinesis (Carrion-Castillo et al 2013;Tarkar et al 2013). In utero gene knockdown in rats has been a major strategy for examining the role of dyslexia candidate genes in brain development (Szalkowski et al 2012;Threlkeld et al 2007;Gabel et al 2011).…”