The Role of Neural and Genetic

Processes in Learning to Read

and Specific Reading Disabilities:
Implications for Instruction
Jessica A. Church ABSTR ACT
The University of Texas at Austin, USA To learn to read, the brain must repurpose neural systems for oral language
and visual processing to mediate written language. We begin with a descrip-
tion of computational models for how alphabetic written language is pro-
Elena L. Grigorenko cessed. Next, we explain the roles of a dorsal sublexical system in the brain
University of Houston, Texas, USA; that relates print and speech, a ventral lexical system that develops the
Baylor College of Medicine, Houston, visual expertise for rapid orthographic processing at the word level, and the
Texas, USA; and St. Petersburg State role of cognitive control networks that regulate attentional processes as chil-
dren read. We then use studies of children, adult illiterates learning to read,
University, Russia
and studies of poor readers involved in intervention, to demonstrate the
plasticity of these neural networks in development and in relation to instruc-
Jack M. Fletcher tion. We provide a brief overview of the rapid increase in the field’s under-
standing and technology for assessing genetic influence on reading. Family
University of Houston, Texas, USA studies of twins have shown that reading skills are heritable, and molecular
genetic studies have identified numerous regions of the genome that may
harbor candidate genes for the heritability of reading. In selected families,
reading impairment has been associated with major genetic effects, despite
individual gene contributions across the broader population that appear to
be small. Neural and genetic studies do not prescribe how children should be
taught to read, but these studies have underscored the critical role of early
intervention and ongoing support. These studies also have highlighted how
structured instruction that facilitates access to the sublexical components of
words is a critical part of training the brain to read.

W
e read because we and others write. We read because only
about 4,000 years ago, it became important to make meaning
out of purposeful scribbles. Through those early scribbles,
human communication changed so it did not have to be face-­to-­face
(Wolf, 2007). Language and sensory processing (usually visual, although
Braille is a tactile example; visual processing is our focus here) are key
components of the reading process. The capacity for language and visual
processing are considered experience-­expectant aspects of the developing
brain that any baby born with typical, healthy sensory organs and brain
will develop. Literacy, in contrast, is considered an experience-­dependent
brain process because without a substantial amount of exposure and
instruction within a culture, the brain will not typically develop this
ability.
Unlike spoken language, reading is acquired. The brain must forge
novel connections between language and visual systems for successful read-
ing, repurposing evolutionarily determined centers. The acquisition of lit-
Reading Research Quarterly, 0(0)
pp. 1–17 | doi:10.1002/rrq.439
eracy rewrites the organization of the brain (Dehaene, 2009). Thus, it not
© 2021 International Literacy Association. surprising that this process can be difficult for many children, and illiteracy

1
is a worldwide problem; although many children come to Pugh et al., 2001). This model was heavily influenced by
school primed to learn to read and engage the brain in the behavioral studies of people who sustained strokes and lost
necessary reorganization, approximately 40% of people specific capacities for reading.
struggle with reading even with sufficient instruction and Another influential set of models, which are derived
opportunity (Seidenberg, 2017). Further, reading difficulties from computational modeling and statistical learning the-
often run in families, speaking to the critical role of genes in ory, are connectionist models. Often referred to as the tri-
the reading process. Genetic processes contribute to indi- angle model, connectionist models explicitly add semantic
vidual differences in learning to read most likely because of processing to the orthographic and phonologic pathways
genes driving the structure and function of the brain and its (Plaut, McClelland, Seidenberg, & Patterson, 1996; Seiden-
malleability. Thus, those with particular genetic profiles, berg, 2017; Seidenberg et al., 2020). As Figure 1 shows,
resulting in particular structural and functional properties dual-­route and connectionist models converge on the idea
of the brain, may be at increased risk for reading difficulties. of brain pathways for lexical and sublexical processing.
In this article, we review what is known about reading in However, in connectionist models, the underlying mecha-
the brain, how changes in reading ability impact the brain, nism is not dual but singular. Word processing occurs as
the heritability and genetic etiology of literacy, and the simultaneous, parallel processes based on the weighted
importance of early experiences and education for develop- connections of different components of the word. As neu-
ing literacy. The development and improvement of literacy ral networks are trained through exposure and feedback,
in a person offers a remarkable opportunity to study the different orthographic units (words) activate different
brain’s plasticity for a novel skill, and the impact of genes and brain patterns. Training and feedback lead to the develop-
environmental factors on that development. This prospect is ment of computational rules that become implicit and
true in typically developing readers, struggling readers, and automatic. The relation of orthography and phonology is
those identified with the term specific reading disability learned because the brain is exposed to a visual representa-
(SRD), encompassing both word-­and text-­level difficulties tion and encodes pronunciation of the word. Feedback is
in reading (American Psychiatric Association, 2013). received on the correct pronunciation. This iterative process
There are multiple ways different cultures have repre- continues as the strength of connections grows among the
sented language through writing. Writing systems gener- different units of the word: Orthographic, phonological,
ally fit into one of three classes: alphabetic (a mapping of and semantic weights for each word are strengthened and
symbols to sublexical units, such as phonemes), syllabic (a become more implicit and automatic (J.S.H. Taylor, Rastle,
mapping of symbols to syllable), or logographic (a map- & Davis, 2013).
ping of symbol to word or morpheme), although in some
languages, the symbol can map to single or multiple pho-
nemes depending on the context (e.g., akshara units; Nag,
2014; Perfetti & Dunlap, 2008). Because the bulk of neuro- Reading and the Brain
biological research has addressed alphabetic writing sys- As understanding of the brain has grown, theoretical mod-
tems, in the literature review, we focus on those research els of reading have been related to engagement of specific
findings. The reader is urged to consider the growing num- brain regions during the reading process. Brain regions
ber of studies of nonalphabetic written languages and to that are important for reading are known because of stud-
not presume that all results discussed here hold across dif- ies of reading problems after brain damage (e.g., stroke)
ferent writing systems (Share, 2014). and, in the last quarter century, because of noninvasive
neuroimaging tools. Neuroimaging tools such as func-
tional magnetic resonance imaging (fMRI) allow unprec-
Models of the Reading Process edented access to populations that do not typically experience
stroke or other types of brain damage (i.e., children, young
Multiple influential models of reading have been proposed adults). From these studies of changes in the oxygenated
based on intensive and careful studies of reading perfor- blood flow in the brain during reading-­related tasks in
mance in both humans and artificial (computer) systems English and other alphabetic languages, the field has
(Dehaene, 2009; Seidenberg, Cooper Borkenhagen, & learned that reading engages the left hemisphere of the
Kearns, 2020). One is the dual-­route model, which pro- brain more than the right hemisphere, which is similar to
poses that every word is processed simultaneously by other aspects of language processing.
orthographic (lexical; word recognition) and phonological When learning to read, a student must understand that
(sublexical; sound-­it-­out) processing streams, with fluent symbols represent particular units of a language. Early
reading relying more on rapid orthographic processing readers of alphabetic written languages must make the
and early reading relying more on the phonological process- association to the phonological structure of speech explicit
ing stream (Church, Coalson, Lugar, Petersen, & Schlaggar, and apply it to print: first at a sublexical level and then in
2008; Coltheart, Rastle, Perry, Langdon, & Ziegler, 2001; larger and larger units; this is known as the alphabetic

2 | Reading Research Quarterly, 0(0)

FIGURE 1
Two Proposed Paths of Reading in the Brain: the Dorsal, Phonographic Route and the Ventral, Orthographic Route
(Dark Arrows)

Note. Key regions of the reading brain are indicated on the left hemisphere. The color figure can be viewed in the online version of this article at
[Link]

principle (Liberman, 1996). This is easier (and faster) to the middle temporal and inferior parietal regions is indi-
learn for orthographies in which symbols map consistently rect and inefficient for accessing meaning at any kind of
onto particular sounds (e.g., Italian) than in English, in speed; still, it is the only way a nonskilled reader can make
which letter symbols frequently represent different sounds sense of print as words. The new reader has to explicitly
depending on a word’s context (e.g., the a in want vs. wait). connect what words look like with how they sound. The
Experience with reading eventually leads to the rapid lexi- lexical, ventral, or lower, system for reading (see Figure 1)
cal processing and immediate orthographic access to develops almost simultaneously in the left occipitotempo-
meaning common to dual-­route and connectionist mod- ral region of the brain and takes advantage of an existing
els. As Figure 1 shows, this early, effortful sublexical pro- evolutionary system for visual processing, including faces
cessing takes a dorsal, or higher, route through the brain and objects (Vogel, Miezin, Petersen, & Schlaggar, 2012).
from the back of the brain (where visual processing As soon as the emerging reader begins to make sense of
occurs) forward. The sublexical system traveling through words as forms, this system begins to organize as a rapid

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction | 3
orthographic processor based in part on the statistical proper- seen in reading-­related brain regions (often in the left
ties by which letters and letter combinations occur, consistent hemisphere) relative to nonstruggling readers seem to
with connectionist models (Dehaene, Cohen, Morais, & Kolin- decrease, with brain activity related to reading improve-
sky, 2015). The ventral system requires considerable exposure ment relates to normalization of previously decreased
to print in order to reorganize for reading. If access to print is activity (for a summary, see Fletcher, Lyon, Fuchs, &
delayed, as is the case for many children at risk for reading dif- Barnes, 2019). Relatedly, stronger readers appear to
ficulties, these systems do not receive the early experience have more consistent engagement of reading-­related
needed to optimally create the expertise for rapid processing of regions from trial to trial (Malins et al., 2018). Second,
print. These two different sets of brain regions align well with some studies have found evidence of right-­hemisphere
the dual-­route and connectionist models of reading, with the engagement increasing in struggling readers who go on
triangle model adding a set of semantic-­related brain regions to experience improvement (Hoeft et al., 2011; Nugiel
(generally also located in the temporoparietal cortex but shown et al., 2019; B.A. Shaywitz et al., 2004). This greater en­­
to be widely distributed; Huth, de Heer, Griffiths, Theunissen, gagement of the right hemisphere in the reading pro-
& Gallant, 2016; Seidenberg, 2017). cess is most often interpreted as a potential compensatory
These models and the corresponding brain systems or alternate mechanism by which the brain attempts to
make specific predictions about where differences in an improve reading, when the original pathways are not
alphabetic writing system should be seen in struggling optimal.
readers relative to proficient readers. Some neuroimaging Third, some studies have begun to expand beyond a
studies have focused on structural differences in the brains focus on reading-­related regions of the brain to other brain
of different groups of people (i.e., struggling and typical networks (e.g., those brain regions related to cognitive
readers). In structural analyses, researchers have compared control, or brain regions known as default regions because
brain region size, thickness, or the white matter fiber bun- they typically show negative signal during tasks when other
dles that connect regions to one another. Many of the stud- regions exhibit positive signal). These studies have found
ies found differences in the structure of reading-­related that reading-­related change over time involves changes in
brain regions in those who struggle to read (e.g., Black these nonreading networks as well, possibly related to the
et al., 2012; Qi et al., 2016; Richlan, Kronbichler, & Wim- maturation of controlled attention, or reflecting change in
mer, 2013; Williams, Juranek, Cirino, & Fletcher, 2018). effort or motivation over time (Aboud, Barquero, & Cut-
Early in the use of fMRI, functional brain analyses of ting, 2018; Hoeft et al., 2011; Nugiel et al., 2019). Engage-
reading in older children and adults established that strug- ment of these additional brain regions in the reading
gling readers engage these reading-­related brain regions less process may depend on the type of reading task being
than their nonstruggling peers do (Eden et al., 2004; B.A. studied; reading comprehension tasks may be more likely
Shaywitz et al., 2002; S.E. Shaywitz et al., 1998). Much work to engage the brain’s cognitive control regions related to
has subsequently expanded on this initial finding of de­­ reading ability (Aboud, Bailey, Petrill, & Cutting, 2016;
creased engagement, studying functional brain activity in Meyler et al., 2007; Patael et al., 2018; Roe et al., 2018).
children in different types of reading tasks, such as reading Interestingly, differences in the engagement of these non-
comprehension (Meyler et al., 2007; Roe et al., 2018), or reading networks between struggling and nonstruggling
activity related to change from reading interventions (Bar- readers, or in struggling readers over time, are apparent
quero, Davis, & Cutting, 2014; Hoeft et al., 2011; Nugiel et al., only during reading tasks; cognitive control tasks that do
2019; Odegard, Ring, Smith, Biggan, & Black, 2008; Turkel- not require reading do not differentiate good and poor
taub, Gareau, Flowers, Zeffiro, & Eden, 2003). Thus, in recent readers (Nugiel et al., 2019; Roe et al., 2018).
years, research has focused less on if or where reading diffi-
culties are seen and more on complicated questions such as Prereaders
how the reading brain changes over age or with skill change,
Studies of brain structure have tested young children who
the impact of learning gains or loss, and the impact of
are at familial risk for reading problems or have delayed
genetic risk or instructional approach on the reading brain.
language onset, prior to the start of reading instruction
(prekindergarten), and found brain differences even in
very young children (Myers et al., 2014; Ozernov-­Palchik
Changes in Literacy et al., 2019; Raschle, Chang, & Gaab, 2011; Saygin et al.,
and Changes in the Brain 2013; Vandermosten, Hoeft, & Norton, 2016). These types
of studies are important because they can begin to separate
Struggling Readers Over Time more causal brain mechanisms from compensatory mech-
There are three primary findings from studies of neural anisms, as both are likely present in older readers. For
changes in struggling readers related to time or intervention. example, one study reported altered sulcal (grooves in the
First, in over 20 studies, when reading improves, differences brain) patterns in prereaders at risk for reading problems

4 | Reading Research Quarterly, 0(0)

(Im, Raschle, Smith, Grant, & Gaab, 2016). There have also fusiform gyrus becomes increasingly specialized for read-
been findings relating the brain’s white matter organiza- ing, as is seen in younger readers. There is no loss of other
tion in young children to their later reading success (e.g., capacities, and acquiring literacy actually enhances other
Zuk et al., 2020). Further, studies have shown that the skills, possibly due to the development of the neural cir-
brain’s white matter undergoes ongoing changes related cuitry mediating reading (Dehaene et al., 2010). Many
to reading skill acquisition over time (Travis, Adams, studies have focused on the role of the ventral system via
Kovachy, Ben-­Shachar, & Feldman, 2017; Vandermosten the fusiform gyrus (the bottom cortex traveling from the
et al., 2015). back, visual areas of the brain forward toward the tempo-
Analysis of brain structure of very young children ral, or side, areas; see Figure 1) as an interface between
with MRI is possible because children can watch a movie vision and language. Better literacy in adults is typically
or otherwise relax (even sleep) during the MRI. It remains characterized by faster visual discrimination of letter and
challenging to study brain function using MRI in very word stimuli, as well as a growing specialization of the left
young children (ages 0–­6 years) because of the simultane- fusiform cortex for word and letter stimuli with gains in
ous demands of holding still and responding to a task. literacy (López-­Barroso et al., 2020; Pegado et al., 2014).
However, researchers have already been working on this Again, the picture of reading as an acquired skill that reor-
scientific frontier with increasing success (e.g., Centanni ganizes the brain is apparent in any learner exposed to for-
et al., 2019; Kersey, Wakim, Li, & Cantlon, 2019; Turesky, mal reading instruction, regardless of age.
Vanderauwera, & Gaab, 2021; Wang, Joanisse, & Booth, Learning to read has been characterized as learning a
2018; Weiss, Cweigenberg, & Booth, 2018; Yamada et al., second language (Seidenberg et al., 2020). In this respect,
2011). These studies of brain function in young prereaders another approach to understanding literacy-­related changes
and early readers have been able to capture how parts of is to ask adults to learn to read a new language (J.S.H. Tay-
the brain’s reading network develop in tandem with read- lor, Davis, & Rastle, 2017; Younger & Booth, 2018; Zhao, Li,
ing ability and reshape the field’s understanding of brain Elliott, & Rueckl, 2018). Notably, adults learn novel written
specialization and plasticity over age and experience (Cen- languages best through a print-­to-­sound teaching strategy,
tanni et al., 2018; Dehaene-­Lambertz, Monzalvo, & Dehaene, consistent with child learning studies (J.S.H. Taylor et al.,
2018; Yamada et al., 2011). Further, there are other tech- 2017). Further, novel language learning can capture and
niques that have long been used to study functional brain explore differences seen in cross-­cultural studies of lan-
activity in young children. Some fMRI studies have com- guage and reading processing across different age groups
plemented ongoing electroencephalography studies using (e.g., syllabic vs. letter-­level symbolism; Hirshorn, Wrencher,
event-­related potentials of prereaders and young readers Durisko, Moore, & Fiez, 2016).
(Bach, Richardson, Brandeis, Martin, & Brem, 2013; Brem
et al., 2010; Hämäläinen et al., 2013; Hong et al., 2018; Ste- The Role of Individual Differences
vens et al., 2013), showing that certain early sound and let-
ter processing-­ related activity relates to later reading Although we have described how the brain reorganizes to
abilities. support literacy, not all brains are equally adept at learning.
Studies of individual differences in reading using neuro-
imaging have related out-­of-­scanner (e.g., school-­based,
Adult Illiteracy standardized) reading measures of each participant to a
What happens in the brains of individuals who do not brain area’s size (e.g., Torre, Matejko, & Eden, 2020), white
learn to read until later in life? A number of studies have matter robustness (e.g., De Vos et al., 2020), or the level of
researched brain activity related to illiteracy or literacy activity during a given fMRI task (e.g., Roe et al., 2018). For
abilities in adults (Cachia et al., 2018; Pegado et al., 2014; these analyses, it is important to carefully consider both
Resende et al., 2018). Adults who, for a variety of reasons, sampling size and variability within the measures being
did not have the opportunity or ability to learn to read as compared, as both meaningfully impact sensitivity to
children can be invaluable participants in research that detect statistically significant and reliable effects. It is also
improves the field’s understanding of plasticity in the critical to not evaluate individual differences within a
mature brain (López-­Barroso et al., 2020). Dehaene and region already shown to have a statistically significant
colleagues (2015) reported that the neural network that group effect (i.e., this is a statistical error of double-­dipping;
emerges with instruction for children and adolescents also Button, 2019; Kriegeskorte, Simmons, Bellgowan, & Baker,
emerges in adults acquiring reading skills for the first time. 2009).
Due to reduced and late exposure, automaticity does not Understanding of individual differences in reading via
emerge as quickly because print exposure is insufficient to neuroimaging has also benefited from multivariate tech-
adapt the ventral systems. However, engagement of the niques such as multivariate pattern analysis, which can test
dorsal system is apparent with the onset of instruction. for patterns across single or multiple data types to predict
The ventral system also begins to reorganize. The left reading (e.g., Kristanto, Liu, Liu, Sommer, & Zhou, 2020),

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction | 5
or categorize or even identify individuals or their family articles surfaced, allowing for heightened development
members from a group (e.g., Demeter et al., 2020). More within the field. It is important to note the following influ-
mobile neuroimaging technologies, such as functional ential publications.
near-­ infrared spectroscopy, may make acquiring more Major gene models—­recessive (Lewitter, DeFries, &
diverse, longitudinal developmental samples easier, although Elston, 1980), dominant (Gilger, Borecki, DeFries, & Pen-
each technology has its own set of limitations (e.g., func- nington, 1994; Pennington et al., 1991), and additive (Pen-
tional near-­infrared spectroscopy cannot currently analyze nington et al., 1991)—­and polygenic models (Pennington
subcortical structures). et al., 1991) are noteworthy because of their alignment
Critically, child engagement of reading-­related brain with varying sets of family data. Although not maintained
regions has been associated with parental reading ability, within the modern findings, these ideas are important to
pointing to the heritable nature of many reading compo- this line of research for multiple reasons. For example, this
nents and the importance of the home reading environ- research defined reading difficulties through two key
ment (Horowitz-­Kraus, Hutton, Phelan, & Holland, 2018). lenses: qualitative phenotypes and quantitative pheno-
These biological and environmental constraints lead to types, a notable approach. Additionally, the varied results
individual differences in the success people experience in generated by this research have illuminated the diversity of
responding to reading instruction, and highlight the need the genetic mechanisms of reading and reading disability.
to consider learners individually, especially in relation to Currently, new analytical approaches to this research high-
the type and intensity of reading instruction. However, light the involvement of multiple genes most likely of
these individual differences are quantitative, not qualita- moderate to low effect sizes (Hsu, Wijsman, Berninger,
tive, and exist on a continuum. They are a matter of degree, Thomson, & Raskind, 2002; Naples, Chang, Katz, & Grigo-
not kind. The nature of these constraints and how indi- renko, 2009; Wijsman et al., 2000). Finally, because varied
vidual differences manifest becomes clearer when consid- degree-­of-­genetic relationships samples from the field are
ering genetic influences on learning to read. available, estimates of relative risk (Ziegler et al., 2005)
consistent with the heritability estimates for (a)typical
reading and related traits have been generated.
The numerous genetically informed samples acquired
The Heritability of Learning have allowed the field to grow significantly (i.e., twins or
to Read and Reading Disabilities other siblings, nuclear and extended families). This has
provided key information on various issues surrounding
A Brief History of the Research the topic. With that, more accurate estimates of heritability
The moment modern culture began to require literacy as a are now available for reading performance and reading-­
means of inclusion in the labor market, it became impor- related skills. Importantly, the vastly available literature can
tant to understand that not all people are able to become and has been meta-­analyzed, and results reveal that when
proficient readers with the same success; not all people’s error variance is noted, heritability estimates are between
experience with learning how to read is the same (Kerr, 41% and 74% for reading ability and up to 90% for reading-­
1897). Teachers cannot guarantee that their method of related skills (Grigorenko, 2004). Estimates of heritability
delivering reading instruction will reach each student are not controlled by sex (Hawke, Wadsworth, Olson, &
equally, because students’ reading abilities vary. Early stud- DeFries, 2007), but other factors, such as age (Byrne et al.,
ies about such a variation in reading abilities brought up 2009) and ethnicity (Grigorenko, Ngorosho, Jukes, &
the idea that gaps in ability could be innate (J.H. Fisher, Bundy, 2006), come into play. Furthermore, heritability
1905, 1910; Hinshelwood, 1900, 1902, 1907; Stephenson, estimates differ in relation to the severity of difficulties, in
1904, 1907; Thomas, 1905). Later, positions on familiality, that it is more sizable in groups with major deficits (Hawke
heredity, and reading ability surfaced (Hallgren, 1950) et al., 2007) and higher IQ (Wadsworth, Olson, & DeFries,
based on evidence highlighting the brain’s involvement in 2010) and increases nonlinearly as children age (Byrne
reading difficulties (Orton, 1939). et al., 2005; Kovas et al., 2013; Samuelsson et al., 2007;
Since the late 20th century, scientists have utilized ­Wadsworth, Corley, Hewitt, & DeFries, 2001).
Hallgren’s (1950) ideas surrounding the genetic factors The foundation of quantitative genetics indicated that
that relate to and potentially influence reading difficulties. heritability is most influential when the environment is
This scientific journey has been as structured as possible, uniform and beneficially primed for people to acquire
given various limitations, such as the lack of diagnostic reading and reading-­related sills. Alternatively, environ-
materials surrounding genetics and reading difficulties, ments that lack such support do not allow people to convey
the price and availability of necessary associated (molecu- their genetic potential for reading. This has been highlighted
lar genetic) technologies, and the availability of analytical in literature associated with teaching instruction (J. Taylor,
methods necessary to appraise the role of the genome in Roehrig, Soden Hensler, Connor, & Schatschneider, 2010),
reading-­related difficulties. By the early 1980s, pioneering parental education (Friend et al., 2009), and socioeconomic

6 | Reading Research Quarterly, 0(0)

status (SES; Hart, Soden, Johnson, Schatschneider, & Tay- support of which in the field of SRD is, although strong,
lor, 2013). rather circumstantial than systematic. To describe the re­­
Finally, Smith, Kimberling, Pennington, and Lubs search noting both hypotheses, we provide a brief intro-
(1983) highlighted genetic factors and interpreted the her- duction on the terminology, conceptual apparatus, and
itability of reading and reading-­related skills into specific common grounds on which the corresponding studies
molecular mechanisms. This one-­of-­a-­kind report insti- have been generated.
gated ongoing research pertaining to the discovery of spe- The first draft of the human genome sparked a decade
cific molecules and their pathways that set the standard for of studies surrounding the genetic makeup of common
sociocultural construction of the reading brain. human traits/disorders and has resulted in a number of
understandings. For example, it is not apparent that the
statistical power of genome-­wide association studies of
Molecular Genetic Aspects of Learning complex traits/diseases, even with sample sizes that were a
to Read and Reading Difficulties great deal larger than previously employed (e.g., thousands
Similar to many other complex disorders, the field of of cases and controls), remains low (Manolio, Brooks,
molecular genetic research into (a)typical reading has been & Collins, 2008; Rodriguez-­Murillo & Greenberg, 2008;
dominated by two major models of the overall genetic Tenesa et al., 2008; Wellcome Trust Case Control Consor-
architecture of complex human traits. The elemental differ- tium, 2007).
ence between these models lies in the identification of the To address this issue, more robust samples have been
disability and the interpretation of normal variation in requested (Manolio, 2010), although disagreements regard­­
reading performance. Genetic studies of SRD have recently ing the potential yield of these calls have arisen (Stein &
been dominated by the common disorder–­common vari- Elston, 2009). The attempt to comprehend the heterogeneity
ant (CDCV) hypothesis that SRD arises on the polygenic has resulted in a growing interest in the role of rare genetic
background: The inheritance of multiple common genetic variants in the etiology of complex disorders (Ahituv et al.,
risk variants are individually characterized by small effect 2007; Cohen et al., 2004, 2006; Ji et al., 2008; Romeo et al.,
sizes but collectively represent a certain liability threshold 2007, 2009; Zhu, Feng, Li, Lu, & Elston, 2010). Often, the
above which the disability is manifested. It is also assumed effect of a rare variant is limited to specific isolated families
that some of these risk variants are general to all facets of or individuals, thus assuming the presence of many hetero-
SRD and, perhaps, to SRD and other learning difficulties, geneous rare variants, both transmitted in families and aris-
such as with math skills (Plomin & Kovas, 2005), whereas ing de novo, the large-­effect (Gorlov, Gorlova, Sunyaev,
others are SRD-­specific and even reading component–­ Spitz, & Amos, 2008) impact of which prompts homoge-
specific (Naples et al., 2009). These partial overlaps of risk neous (or semihomogeneous) behavior manifestations.
variants can explain substantial, but far from 1.0, genetic Upon the completion of the first draft of the human
correlations between different reading-­related componential genome (International Human Genome Sequencing Con-
processes, both in typical reading and SRD. These partial sortium, 2001), the assumption in the field was that delin-
overlaps can also explain differential heritability estimates eating the main type of genomic/genetic variation between
for different reading-­related componential processes and two individual human beings would be captured primarily
their fluctuations when other sources of variance (e.g., age, (although not exclusively) by their complement of single
ethnicity, SES, quality of teaching) are considered. Finally, nucleotide polymorphisms (SNPs; a common variation in
the CDCV hypothesis assumes the continuity between each of the nucleotides—­adenine, thymine, cytosine, or
typical and atypical states (i.e., a single underlying trait that guanine—­of the DNA sequence). This type of variation
defines various states), as common risk variants are present was expected to affect approximately .1% of the total
in the general population at levels below the liability thresh- genomic sequence. Yet, ensuing research has not con-
old, and this presence guarantees a progression of reading firmed that delineation and, instead, has revealed copy
performance. number variation and structural variation (CNV/SV1) to
The common disorder–­rare variant (CDRV) hypoth- be the main sources of variation among humans. The
esis, on the contrary, assumes that almost each case is essence of this variation is complicated: In addition to
caused by a single rare variant of large effect size and that SNPs, each genome contains an abundance of tiny inser-
these variants can materialize in different genes in differ- tions and deletions (indels: the insertion or deletion of
ent families/individuals. This hypothesis can explain the bases in the DNA sequence longer than one nucleotide)
powerful findings of the genetic foundation for specific and a plethora of CNV/SV, where entire blocks of the
families and the lack of generalizability of these findings DNA sequence, ranging in size from just 1 KB to several
to heterogeneous SRD samples. Although both hypothe- MB, have been inserted, deleted, inverted, or somehow
ses and their multiple versions are implied in the litera- translocated (Conrad et al., 2010).
ture on SRD, they have not been methodically tested. Similar to this basic realization depicting the nature of
This is true for the CDRV hypothesis, the evidence in normal variation in the human genome, more studies have

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction | 7
linked not only point mutations and functional SNPs but both catalogs are likely to continue growing (Rubenstein,
also events such as CNV/SV to phenotypic effects, both in Matsushita, Berninger, Raskind, & Wijsman, 2011).
fit and unfit individuals. Yet, technology has only recently To date, multiple genome-­wide screens for SRD and
become available that may permit the linking of compre- reading-­related difficulties (e.g., Brkanac et al., 2008; de
hensively mapped genotypes consisting of all classes/sizes Kovel et al., 2004; Eicher et al., 2013; Fagerheim et al., 1999;
of variation events to clinical phenotypes. Normal human Field et al., 2013; S.E. Fisher et al., 2002; Gialluisi et al., 2014;
genomic variation must be considered when attempting to Igo et al., 2006; Kaminen et al., 2003; Luciano et al., 2013;
interpret complex traits/disorders, if indeed a complex Meaburn, Harlaar, Craig, Schalkwyk, & Plomin, 2008;
trait/disorder is caused not by a single genetic event of Nopola-­Hemmi et al., 2002; Raskind et al., 2005; Roeske
strong effect but by a combination of variants, each of small et al., 2011; Svensson, 2011) have been reported. These
effect, or by a rare variant of medium strong effect embed- studies, driven by the CDCV hypothesis, utilized hundreds
ded in a background of modifying normal variants (i.e., the of thousands of SNPs, as technology and cost allowed.
merger of the CDCV and CDRV hypotheses). Studies also have focused on select areas of the genome.
We hope that our explanations have explained the The selection of these regions is usually determined either
stockpile available to the genome to control both typical by a previous whole-­ genome scan or by a theoretical
and atypical development of a skill. Reading development hypothesis capitalizing on SRD and its componential pro-
is obviously not an exception, and the genome has cesses (Skiba, Landi, Wagner, & Grigorenko, 2011).
recruited many tricks that demonstrate the diversity of Nevertheless, some researchers have decided on candi-
human brain structure and function. This is reflected, in date regions through different methods, such as through a
turn, in the diversity of human development in general known chromosomal aberration (i.e., through the verifica-
and reading development in particular. Next, we present a tion of the CDRV hypothesis). For instance, Denmark
brief overview to illustrate how the two hypotheses, CDCV evaluates all newborns for macrochromosomal changes
and CDRV, may be exemplified in the modern literature (e.g., large rearrangements). With those data, researchers
on the molecular genetic bases of typical and atypical have evaluated those who have such macrochromosomal
reading. changes for the presence of SRD as they participate in early
schooling (Buonincontri et al., 2011). The conjecture is
that a gene affected by such a chromosomal abnormality is
Recent Developments associated with SRD in some way. ROBO1 (Hannula-­
in Genetic Studies of Reading Jouppi et al., 2005), DYX1C1 (Taipale et al., 2003), and
and Reading Difficulties SEMA6D2 (Ercan-­ Sencicek et al., 2012) are candidate
CDCV has leveraged the frequent manifestation of reading genes for reading difficulties that have been illuminated by
difficulties in the general population, whereas CDRC has this process. All of these genes have been detected through
capitalized on the infrequent manifestation of severe read- studies of isolated families (Taipale et al., 2003) or even
ing difficulties existing within extended families highly individual cases (Ercan-­Sencicek et al., 20123).
dense with SRD. These studies (see Grigorenko, 2005) can It is important to stress that such large variations are
be broken down into a number of key overlapping catego- relatively rare (e.g., <1% of the general population), and
ries, by the type of samples they engaged (i.e., genetically the underlying assumption here is that the identification of
unrelated cases/probands and matched controls vs. family such rare variants will provide a clue for future studies of
units such as siblings or nuclear and extended families) and the gene(s) affected by this structural alteration, or the
by the type of genetic units they targeted (i.e., specific genes pathway in which this gene(s) is(are) involved. The idea is
or specific genetic regions vs. the whole genome). For all that once a rare variant is identified and associated with a
approaches combined, there are currently references to particular trait (e.g., reading), there is a need to investigate
approximately 20 (Schumacher, Hoffmann, Schmäl, Schulte- common variance in the gene/region that was impacted by
­Körne, & Nöthen, 2007) potential genetic susceptibility loci this rare variant. In the field of reading, an example of such
(i.e., regions of the genome that have demonstrated a statis- a transition from a rare variant to a continuous trait is the
tically significant linkage to SRD; in most cases, these research on the ROBO1 gene (Bates, Luciano, Montgom-
regions consist of more than one and often hundreds of ery, Wright, & Martin, 2011).
genes) and six or more official (Grigorenko & Naples, 2009; Nine candidate regions of the human genome have
Peterson & Pennington, 2012) and many unofficial, but been involved in SRD. These regions are recognized as
recognized, candidate genes (i.e., genes located within sus- SRD candidate regions; they are abbreviated as DYX1–­
ceptibility loci that have been statistically associated with DYX9 (DYX for dyslexia, a term often used to refer to SRD)
SRD). None of these loci or genes have been either entirely and refer to the regions on chromosomes 15q, 6p, 2p, 6q,
welcomed or rebuffed by the field. Moreover, new regions 3cen, 18p, 11p, 1p, and Xq, respectively. Each of these
and candidate genes are being submitted regularly, and regions harbors dozens of genes, and some of them have

8 | Reading Research Quarterly, 0(0)

been named as risk genes for SRD: two for the 15q region, that affect vulnerable youth, and contribute to a more rounded
DYX1C1 and SEMA6D; two for the 6p region, KIAA0319 understanding of how reading develops at different levels
and DCDC2; two for the 2p region, C2Orf3 and MRPL19; of explanation. Gabrieli also argued that brain and genetic
and one for the 3cen region, ROBO1. Although the field has markers could facilitate early intervention because they
not yet converged on firm candidates, it is remarkable, and may identify risk at earlier ages than behavioral measures
of scientific interest, that of the current candidate genes for would, and may be more precise because the error vari-
SRD, five genes (DYX1C1, SEMA6D, KIAA0319, DCDC2, ance is smaller.
and ROBO1) are involved in biological functions of neuro- In a different vein, Protopapas and Parrila (2018) ques-
nal migration and axonal crossing. Thus, all of these genes tioned whether neuroimaging studies can show that SRD
are plausible candidates for understanding the pattern of is a neurodevelopmental disorder or not. Because neuro-
brain functioning in those with reading difficulty. imaging studies largely have demonstrated that differences
Importantly, more genes have been reported as pre- in brain structure and function are quantitative in nature,
sumed additions to this list (e.g., Buonincontri et al., 2011; perhaps they should not be regarded as atypical or abnor-
Ercan-­Sencicek et al., 2012; Gialluisi et al., 2019; Newbury mal and, as such, do not justify labeling SRD, or dyslexia, as
et al., 2011; Scerri et al., 2010). At this point, the field con- a disorder per se. In response, Fraga González, Karipidis,
tains both support and lack of support for the involvement and Tijms (2018) argued that SRD should be considered a
of each of these genes; thus, the findings are somewhat dif- disorder because it has adverse consequences for adjust-
ficult to interpret. In addition, there is an ongoing debate ment and long-­term consequences for quality of life. In
regarding the specificity of the impact of SRD-­related addition, the researchers noted that the neural networks
genes. Some of the genes identified as candidate genes for mediating reading in people identified with SRD were
SRD have been featured in other learning disabilities (e.g., atypical, which in turn supported the use of the term disor-
Mascheretti et al., 2014), as well as in other developmental der when referring to SRD. Like Gabrieli (2016), Fraga
disorders and unrelated health difficulties, such as atten- González and colleagues argued that neuroimaging stud-
tion deficit hyperactivity disorder and autism spectrum ies help demonstrate that reading difficulties have a bio-
disorders (e.g., Price et al., 2020). Finally, other genes logical basis in the brain and that brain disorders can exist
known to be associated with a variety of cognitive pro- on a spectrum of (dis)ability.
cesses have been shown to be associated with reading and Many developmental and medical disorders represent
other cognitive functions, thus questioning the specificity dimensional phenomena in which the defining attributes
of the genetic sources of individual differences for varia- are normally distributed (Ellis, 1985). SRD is the lower end
tion in reading and in related brain functions (Jasińska of an unbroken continuum of reading ability. The thresh-
et al., 2016; Landi et al., 2013). old for determining SRD is arbitrary and dependent on
demonstrations of adverse effects on outcomes (see
Fletcher et al., 2019). However, the same can be said for
other heritable neurodevelopmental disorders, such as
Implications for Reading attention deficit hyperactivity disorder, where the key attri-
Instruction and Practice: butes of inattention and hyperactivity-­impulsivity are nor-
mally distributed in the population. Similarly, medical
Some Controversy disorders such as obesity and hypertension are defined by
There is controversy over the implications of neuroimaging normally distributed attributes and are considered disor-
and genetic research for education. We think that the pri- ders when health consequences emerge in relation to
mary contribution thus far of these advances is at the level objective indices of maladaptation (e.g., stroke, diabetes).
of mechanism. Bowers (2016) was critical of applications of Dimensionality does not mean that reading is not heri-
cognitive neuroscience to education, because there were no table or brain based, and does not mean that environmental
clear implications in the brain data for instruction. He factors, such as the quality of the home environment for lan-
argued that claims for the value of educational neurosci- guage, literacy, and instruction, are not contributory. There
ence were exaggerated and that there was little about is malleability in both the neural and environmental contri-
instruction that could not be explained at a behavioral level. butions that can be manipulated to shift the reading con-
Bowers also argued that demonstrations of the malleability tinuum upward in performance so lower levels of reading
of the brain in response to reading instruction were irrele- ability are less maladaptive for individuals in our society.
vant because all that was needed was the evidence from Literacy and SRD should not be considered as a skill or dis-
standard reading tests that improvement had occurred. order that represents categories that are static and where the
In responding to Bowers (2016), Gabrieli (2016) noted goal is to identify abnormalities for treatment. Rather, the
that expecting basic neuroscience research to directly inform goal should be to shift the entire continuum so outcomes for
classroom teaching was a high bar. Instead, neuroscience lower end readers are less adverse. This means that in order
and genetic research helps in understanding mechanisms to shift the reading continuum of abilities, efforts should

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction | 9
focus on the entire spectrum of instruction, from general alternate pathways are not apparent when only behavioral
education to remedial intervention. measures are used (Church, Petersen, & Schlaggar, 2010).
These demonstrations of the continuity of reading Neuroimaging also can identify supportive cognitive
ability should alter traditional, static conceptualizations of processes critical for the reading process that may contrast
SRD from a disorder of constitutional origin (Critchley, to behavioral findings. For example, measures of cognitive
1970) to a more contemporary account. Certain heritable control (sometimes referred to as executive functions)
gene combinations put the brain at risk, and certain envi- have weak behavioral relations with reading despite the
ronmental factors, such as high-­quality instruction, reduce evidence of self-­regulation difficulties in many children
this risk. It is helpful to examine the dorsal and ventral who struggle (Cirino et al., 2019). In neuroimaging studies,
reading systems in relation to connectionist models of the there has been clear involvement of regions of the brain
reading process. Paralleling the increasing involvement that involve cognitive control in both decoding (Aboud
of the ventral, lexical system in the brain, as exposure et al., 2018; Horowitz-­Kraus, Toro-­Serey, & DiFrancesco,
increases, implicit learning and self-­teaching (Share, 1995) 2015) and comprehension tasks (Nugiel et al., 2019). Fur-
lead to increasing automaticity and the capacity for directly ther, engagement of nonreading brain regions related to
accessing meaning from orthography (Seidenberg et al., subsequent reading change when behavioral measures of
2020). However, reading is a developmental process in reading did not yet differentiate between individuals (Nugiel
which phonological processing is essential in the initial et al., 2019).
phases. Behavioral research has supported a need for Similarly, genetic research can identify specific genetic
explicit instruction in sound–­symbol relations to access pathways or systems whose function might be responsive
sublexical components of words through phonics, mor- to feedback, globally defined. What this means mechani-
phology, and spelling instruction (Seidenberg, 2017). We cally is that there could be some environmental agents
argue that neuroscience and genetic research has identi- (e.g., repeated practice) that can change biology through
fied mechanisms and concurrent evidence to support this processes such as epigenetic regulation of the genome.
instructional approach. These patterns of expression in the identified pathways
Another example of the relevance of neuroimaging and systems, in turn, will influence the structure and func-
research for reading instruction concerns the importance tion of the brain regions that are engaged in reading.
of early intervention. As discussed earlier, reading involves Clearly, being able to manipulate these mechanisms
knowledge of both the form and meaning of a word, which requires the identification of the components of these
are processed parallel to the act of reading (Perfetti, 2007). mechanisms (i.e., regions of the genome and brain) and
A young child or an adult who has had no formal reading the dynamics of their interaction (e.g., the role of epigene-
instruction cannot recognize the form of the word. The tic processes).
child or adult can match letters, but the word is not an One commonly cited justification for neuroimaging
entity in the person’s visual field unless he or she can link and genetic studies is the earlier identification of SRD risk,
the sublexical components of the word to their pronuncia- another high bar (Gabrieli, 2009). This possibility is appar-
tions. At a neural level, this means accessing and utilizing ent with genetic studies, where sequencing of the genotype
the person’s capacity for oral language, which means teach- could identify genetic variations as early as birth that
ing the dorsal system to learn to link print and sound. Once might establish SRD risk. Yet, because reading is experi-
this learning begins, the ventral system begins almost ence dependent and acquired, only risk can be established,
immediately to reorganize into a rapid orthographic pro- and the environment would play a major role in any actual
cessor. Without sufficient exposure to print, children fall manifestation of SRD. It is not likely that single-­gene defect
behind in their development of a sight word vocabulary; models will arise that account for a large number of SRD
thus, remediation at older ages is slow, and many do not cases. Thus, genetic research is not at a point where clear
develop the automaticity needed to make reading enjoy- manifestation or risk can be established. It has also been
able and effortless. Comparisons of the efficacy of reading suggested (Gabrieli, 2009) that neuroimaging research
instruction with struggling readers have shown much could be more precise in establishing SRD risk in compari-
more effectiveness in or before grade 3 (Connor et al., 2013; son with behavioral studies, but the cost-­effectiveness of
Lovett et al., 2017). Neuroimaging studies have informed such an approach is not apparent. In addition, it has not yet
our understanding of this process and provided some abil- been established that large-­scale screening based on neu-
ity to measure change and timing that supplement and roimaging studies is more precise than behavioral screen-
inform behavioral studies, including that some children ing of risk, even if able to be done earlier than much
improve in reading by generating or giving weight to alter- behavioral testing.
nate neural pathways (Hoeft et al., 2011; Nugiel et al., 2019). As a final example, consider the long-­observed ten-
Neuroimaging studies thus have illuminated the idea of dency for young children to reverse letters and write words
behavioral phenocopy, or the idea that different brain orga- backward. A developmental phenomenon, this tendency
nizations can result in similar behavioral output; these recedes as children grow older but has also (mistakenly)

10 | Reading Research Quarterly, 0(0)

been seen as a marker for SRD because it seems to persist of reading through the brain that depend first on sublexical
in some children. Using neuroimaging, Dehaene and col- linking of language sound to written symbol. Genetic
leagues (2010) showed that in literate adults, the ventral research has identified many potential candidate genes that
pathway for reading, and specifically the left fusiform, is convey genetic risk for SRD, but are also taking genome-­
activated when viewing pictures that are mirrored, but not wide approaches to understand how subtle differences
for mirrored words. In illiterate adults, however, both mir- among people lead to variability in reading ability. Neuro-
rored pictures and words engaged this region. As an adult imaging and genetic research tools are rapidly developing.
learns to read, the activation for reading mirrored images As researchers learn more about genetic risk factors and
in the left fusiform gyrus diminishes; it becomes special- early brain markers, the field grows more able to identify
ized for graphemic processing. From this adult work, we children at risk for SRD earlier and thus more able to inter-
can surmise what is happening in young children, where vene earlier. The field also gains insights into the biological
the left fusiform is not yet specialized; mirrored writing and environmental factors that may allow variability reduc-
and reversals are common until the left fusiform becomes tion in reading ability and boost the effectiveness, type, and
specialized for word processing and are signs of the timing of reading instruction.
remarkable rewiring process that occurs as the brain learns
to read. Neuroimaging and genetic work across different NOTES
ages and different skills thus all have the potential to Some of this work was supported in part by a grant (P50HD052117)
inform understanding of the learning process from un­­ from the Eunice Kennedy Shriver National Institute of Child Health and
skilled to skilled reading, and can potentially explain com- Human Development (NICHD) to the University of Houston for the
Texas Center for Learning Disabilities (principal investigator: Jack M.
monly observed but misunderstood phenomena. Fletcher) and by a grant (18-­18-­00451) from the Russian Science Foun-
dation (principal investigator: Elena L. Grigorenko). The content is
solely our responsibility and does not necessarily reflect the views of the
National Institutes of Health or the NICHD. We thank Tehila Nugiel for
Future Challenges thoughtful comments on an early version of this manuscript, Alice Aizza
and AnnaCarolina Garza for figure assistance, and Nicole Guha and Mei
As this review has hopefully made clear, neuroimaging and Tan for editorial support.
genetic approaches provide a biological level with which to 1
S Vs are comprised of CNVs such as deletions and insertions, as well
understand the mechanisms underlying academic difficul- as copy number neutral events such as inversions and balanced
ties. This level is complementary to cognitive (i.e., neuro- translocations.
psychological testing) and behavioral (i.e., observation) 2
Semaphorins are a large family of proteins, including both secreted and
approaches (Frith, 2001). Biological approaches struggle membrane-­associated proteins, many of which have been implicated as
with similar difficulties as in cognitive and behavioral inhibitors or chemorepellents in axon pathfinding, fasciculation and
branching, and target selection (National Center for Biotechnology
approaches (no objective cut point, multiple sources of Information, 2021).
heterogeneity) but can also provide additional information 3
In this particular case, the proband was originally referred at the age of
that could ultimately help parse some of the diverse pro- 3, as a child with developmental language disorders, but later, at the age
files inherent in reading problems. of 12, he presented with a reading comprehension disorder with intact
One future challenge is to explain sources of heteroge- decoding skills.
neity in neural and genetic data, to identify differences of
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16 | Reading Research Quarterly, 0(0)

 beginning readers of different levels of pre-­literacy abilities: An JESSICA A. CHURCH (corresponding author) is an associate
fMRI study. NeuroImage, 57(3), 704–­713. [Link] professor in the Department of Psychology at The University of
neuro​image.2010.10.057 Texas at Austin, USA; email church@[Link]. Her
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of cognitive control and academic skills, with a particular
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ELENA L. GRIGORENKO is the Hugh Roy and Lillie Cranz
Scientific Studies of Reading, 22(3), 191–­208. [Link] Cullen Distinguished Professor of Psychology at the University
10888​438.2017.1414219 of Houston, Texas, USA; a research-­certified professor in the
Zhu, X., Feng, T., Li, Y., Lu, Q., & Elston, R.C. (2010). Detecting rare vari- Department of Molecular and Human Genetics at Baylor
ants for complex traits using family and unrelated data. Genetic Epi- College of Medicine, Houston, Texas, USA; and a leading
demiology, 34(2), 171–­187. [Link] research scientist at St. Peterburg University, Russia; email
Ziegler, A., König, I.R., Deimel, W., Plume, E., Nöthen, M.M., Propping, [Link]@[Link]. Her research focuses on
P., … Schulte-­Körne, G. (2005). Developmental dyslexia—­recurrence human development in diverse contexts across multiple levels,
risk estimates from a German bi-­center study using the single pro- using methods that integrate behavior, neuroimaging, and
band sib pair design. Human Heredity, 59, 136–­143. [Link]
molecular genetic analyses.
10.1159/00008​5572
Zuk, J., Dunstan, J., Norton, E., Yu, X., Ozernov-­Palchik, O., Wang, Y., …
JACK M. FLETCHER is the principal investigator of the
Gaab, N. (2020). Multifactorial pathways facilitate resilience among
kindergarteners at risk for dyslexia: A longitudinal behavioral and
Texas Center for Learning Disabilities and the Hugh Roy and
neuroimaging study. Developmental Science, 24(1), Article e12983. Lillie Cranz Cullen Distinguished University Chair of
[Link] Psychology at the University of Houston, Texas, USA; email
jackfletcher@[Link]. His research spans disability definition,
Submitted December 20, 2020 classification, neurobiological correlates, and intervention in
Final revision received June 22, 2021 multiple disorders, including learning disabilities and
Accepted June 29, 2021 pediatric brain injury.

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction | 17