Genetic bases of reading disability (Dobrynin et al., 2025)

<p dir="ltr"><b>Purpose: </b>This study investigated the genetic bases of specific reading disability (SRD) by systematically cataloging candidate genes reported as associated with SRD and reading-related processes over the last 4 decades and analyzing their evolutionary conservation, developmental expression patterns, and functional networks to address significant knowledge gaps in understanding the genetic architecture of reading (dis)ability.</p><p dir="ltr"><b>Method: </b>Through a comprehensive literature review, we identified 175 putative SRD (and reading-related processes) candidate genes (hereafter, SRD genes). Using bioinformatic approaches, we analyzed their evolutionary conservation across species, examined their expression patterns in developmental and single-cell transcriptome data sets from the Allen Brain Atlas, and performed functional pathway analyses to identify biological processes associated with these genes.</p><p dir="ltr"><b>Results: </b>SRD genes showed remarkable evolutionary conservation, with enrichment in ancient taxonomic groups. Developmental transcriptome analysis revealed two distinct gene clusters with expression differentiation around 24 postconception weeks: early genes associated with brain morphology development and later genes involved in synaptic signaling. Single-cell analysis identified cell-type–specific expression patterns and protein–protein interaction networks with hub genes potentially coordinating reading-related neural pathways.</p><p dir="ltr"><b>Conclusions: </b>Our findings challenge the notion of the existence of reading-specific genes, suggesting instead that SRD reflects the disruption of ancient evolutionary neural mechanisms operating within human-specific brain architecture. The identification of developmental expression transitions and functional networks provides insight into how genetic variation might impact reading development and offers potential targets for future clinical approaches to the identification and remediation of reading difficulties.</p><p dir="ltr"><b>Supplemental Material S1. </b>SRD Genes - Comprehensive catalog of 175 genes identified as putative candidates for Specific Reading Disability, including Ensembl ID, NCBI ID, and common gene name for reference and cross-database identification.</p><p dir="ltr"><b>Supplemental Material</b><b> S2.</b> Literature Review Methodology – Details on stepwise approach for systematic literature identification, including search criteria, filtering conditions, and resulting paper counts at each stage of the review process.</p><p dir="ltr"><b>Supplemental Material</b><b> S3.</b> Brain Regions in Transcriptome Analysis - Anatomical brain regions examined in the developmental transcriptome dataset with their corresponding acronyms and inclusion status for subsequent analysis.</p><p dir="ltr"><b>Supplemental Material</b><b> S4.</b> Differential Gene Expression Analysis - Complete output from Limma analysis identifying differentially expressed genes across developmental timepoints, with additional classification based on single-cell dataset clustering.</p><p dir="ltr"><b>Supplemental Material</b><b> S5.</b> Prenatal Gene Expression Enrichment - Gene ontology (GO) biological processes significantly enriched among genes upregulated during fetal development, including statistical metrics, pathway information, and gene identifiers.</p><p dir="ltr"><b>Supplemental Material</b><b> S6.</b> Postnatal Gene Expression Enrichment - Gene ontology (GO) biological processes significantly enriched among genes upregulated after birth, including statistical metrics, pathway information, and gene identifiers.</p><p dir="ltr"><b>Supplemental Material</b><b> S7.</b> Evolutionary Selection Analysis - Statistical summary of selection models (branch model, FEL, RELAX) applied to SRD genes, including test statistics and significance values for evolutionary constraint assessment.</p><p dir="ltr"><b>Supplemental Material</b><b> S8.</b> KEGG Pathway Enrichment - Results from gene set enrichment analysis against the KEGG database, highlighting significant biological pathways represented by SRD genes with statistical measures and gene identifiers.</p><p dir="ltr"><b>Supplemental Material</b><b> S9.</b> Reactome Pathway Analysis - Enrichment analysis results using the Reactome database, identifying significant functional pathways represented by SRD genes with corresponding statistical metrics.</p><p dir="ltr"><b>Supplemental Material</b><b> S10.</b> PAML and evolutionary novelty analysis.</p><p dir="ltr"><b>Supplemental Material</b><b> S11.</b> Raw data from HomoloGene, retrieved on 02/05/2023.</p><p dir="ltr">Dobrynin, P., Zeng, Y., Norkina, M., Fedorova, A., Zhuk, A., Grigorenko, E. L. (2025). Four decades of inquiry into the genetic bases of specific reading disability. <i>Journal of Speech, Language, and Hearing Research</i><i>, </i><i>68</i>(11), 5158–5173. <a href="https://doi.org/10.1044/2025_JSLHR-25-00050" rel="noreferrer" target="_blank">https://doi.org/10.1044/2025_JSLHR-25-00050</a></p>