Abstract
Impaired phonological processing is a leading symptom of multifactorial language and learning disorders suggesting a common biological basis. Here we evaluated studies of dyslexia, dyscalculia, specific language impairment (SLI), and the logopenic variant of primary progressive aphasia (lvPPA) seeking for shared risk genes in Broca’s and Wernicke’s regions, being key for phonological processing within the complex language network. The identified “phonology-related genes” from literature were functionally characterized using Atlas-based expression mapping (JuGEx) and gene set enrichment. Out of 643 publications from the last decade until now, we extracted 21 candidate genes of which 13 overlapped with dyslexia and SLI, six with dyslexia and dyscalculia, and two with dyslexia, dyscalculia, and SLI. No overlap was observed between the childhood disorders and the late-onset lvPPA often showing symptoms of learning disorders earlier in life. Multiple genes were enriched in Gene Ontology terms of the topics learning (CNTNAP2, CYFIP1, DCDC2, DNAAF4, FOXP2) and neuronal development (CCDC136, CNTNAP2, CYFIP1, DCDC2, KIAA0319, RBFOX2, ROBO1). Twelve genes showed above-average expression across both regions indicating moderate-to-high gene activity in the investigated cortical part of the language network. Of these, three genes were differentially expressed suggesting potential regional specializations: ATP2C2 was upregulated in Broca’s region, while DNAAF4 and FOXP2 were upregulated in Wernicke’s region. ATP2C2 encodes a magnesium-dependent calcium transporter which fits with reports about disturbed calcium and magnesium levels for dyslexia and other communication disorders. DNAAF4 (formerly known as DYX1C1) is involved in neuronal migration supporting the hypothesis of disturbed migration in dyslexia. FOXP2 is a transcription factor that regulates a number of genes involved in development of speech and language. Overall, our interdisciplinary and multi-tiered approach provided evidence that genetic and transcriptional variation of ATP2C2, DNAAF4, and FOXP2 may play a role in physiological and pathological aspects of phonological processing.
Highlights
Developmental language and learning disorders severely impair children’s abilities in speaking, reading, writing, calculating, and combinations thereof (American Psychiatric Association, 2013)
One cognitive domain commonly involved in the majority of these disorders is phonological processing which refers to the analysis and synthesis of the sound structure of spoken and written language, phonological representations and the rapid access or memorizing thereof
The following criteria were used to screen the literature and had to be fulfilled: (a) Publication date between 01/01/2010 and 23/05/2021, (b) investigation of at least one of the disorders dyslexia, dyscalculia, specific language impairment (SLI), and logopenic variant of primary progressive aphasia (lvPPA), (c) report of at least one human gene as significant original/replicated result (p < 0.05), (d) report of at least one gene as a risk factor for a disorder or trait/phenotype related with the disorder, (e) sample containing more than one individual, (f) sample of European origin to reduce a potential influence of population stratification on our results, (g) study either a linkage analysis, a genome-wide association study (GWAS), or a candidate gene association study
Summary
Developmental language and learning disorders severely impair children’s abilities in speaking, reading, writing, calculating, and combinations thereof (American Psychiatric Association, 2013). Patients with dyslexia, dyscalculia, or specific language impairment (SLI) show deficits in key domains of phonological processing such as phonological awareness, phonological working memory, and/or speeded access to phonological codes during rapid automatized naming, as summarized in Supplementary Table 1. Dyslexia patients perform poorly on phonological working memory (De Carvalho et al, 2014; Child et al, 2019) and show deficits in phonological representations leading to difficulties in phoneme awareness and phonological coding (Pennington and Bishop, 2009). Patients with SLI, especially with a speech sound disorder, exhibit an inadequate phonological realization and use of particular phonemes in spontaneous speech due to impaired phonological awareness abilities and a lower quality of phonological representations (Lewis et al, 2011; Claessen and Leitão, 2012; American Psychiatric Association, 2013). Some studies showed lower scores in SLI in phonological working memory increasing the language difficulties (Torrens and Yagüe, 2016)
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