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

Purpose: 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.
Method: 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.
Results: 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.
Conclusions: 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.
Supplemental Material S1. 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.
Supplemental Material S2. 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.
Supplemental Material S3. Brain Regions in Transcriptome Analysis - Anatomical brain regions examined in the developmental transcriptome dataset with their corresponding acronyms and inclusion status for subsequent analysis.
Supplemental Material S4. 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.
Supplemental Material S5. 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.
Supplemental Material S6. Postnatal Gene Expression Enrichment - Gene ontology (GO) biological processes significantly enriched among genes upregulated after birth, including statistical metrics, pathway information, and gene identifiers.
Supplemental Material S7. 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.
Supplemental Material S8. 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.
Supplemental Material S9. Reactome Pathway Analysis - Enrichment analysis results using the Reactome database, identifying significant functional pathways represented by SRD genes with corresponding statistical metrics.
Supplemental Material S10. PAML and evolutionary novelty analysis.
Supplemental Material S11. Raw data from HomoloGene, retrieved on 02/05/2023.
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. Journal of Speech, Language, and Hearing Research, 68(11), 5158–5173. https://doi.org/10.1044/2025_JSLHR-25-00050

研究目的：本研究针对特定阅读障碍（Specific Reading Disability, SRD）的遗传基础展开探究。通过系统梳理近40年来已报道的与SRD及阅读相关认知过程存在关联的候选基因，并分析其进化保守性、发育表达模式与功能网络，以填补当前在理解阅读（障碍）遗传架构方面存在的显著知识空白。
研究方法：本研究通过全面的文献综述，共筛选得到175个疑似与SRD及阅读相关认知过程相关的候选基因（以下简称SRD基因）。随后采用生物信息学方法，分析这些基因在不同物种间的进化保守性，基于艾伦脑图谱（Allen Brain Atlas）的发育型与单细胞转录组数据集探究其表达模式，并开展功能通路分析以明确这些基因所参与的生物学过程。
研究结果：SRD基因表现出显著的进化保守性，在古老的分类群中富集。发育转录组分析显示，共有两个特征鲜明的基因簇在受孕后24周左右出现表达分化：其中早期基因与脑形态发育相关，晚期基因则参与突触信号传导过程。单细胞分析进一步明确了细胞类型特异性的表达模式，以及以枢纽基因为核心的蛋白质-蛋白质相互作用网络，这类枢纽基因可能协同调控与阅读相关的神经通路。
研究结论：本研究结果挑战了“存在阅读特异性基因”这一观点，转而表明SRD实则是人类特异性脑架构中运作的古老进化神经机制遭到破坏所导致的。本研究对发育表达转换模式与功能网络的解析，为理解遗传变异如何影响阅读发育提供了新视角，同时也为未来用于识别与矫正阅读困难的临床手段提供了潜在靶点。
补充材料S1：SRD基因集——包含175个经筛选得到的SRD疑似候选基因的完整目录，其中涵盖Ensembl编号、NCBI编号以及通用基因名称，用于跨数据库的参考与识别。
补充材料S2：文献综述方法学——详细阐述系统性文献检索的分步流程，包括检索标准、筛选条件以及各审查阶段的文献数量统计结果。
补充材料S3：转录组分析所涉脑区——发育转录组数据集中纳入分析的解剖脑区及其对应缩写与纳入状态说明。
补充材料S4：差异基因表达分析——Limma分析的完整输出结果，可识别不同发育时间点的差异表达基因，并基于单细胞数据集聚类结果进行额外分类。
补充材料S5：产前基因表达富集分析——胎儿发育阶段上调基因中显著富集的基因本体（Gene Ontology, GO）生物学过程条目，包含统计指标、通路信息与基因标识符。
补充材料S6：产后基因表达富集分析——出生后上调基因中显著富集的基因本体（GO）生物学过程条目，包含统计指标、通路信息与基因标识符。
补充材料S7：进化选择分析——针对SRD基因所应用的选择模型（分支模型、FEL、RELAX）的统计汇总结果，包括进化约束评估所需的检验统计量与显著性值。
补充材料S8：KEGG通路富集分析——基于KEGG数据库开展的基因集富集分析结果，明确了SRD基因所代表的显著生物学通路，并附带统计指标与基因标识符。
补充材料S9：Reactome通路分析——基于Reactome数据库开展的富集分析结果，可识别SRD基因所代表的显著功能通路，并附带对应统计指标。
补充材料S10：PAML与进化新颖性分析。
补充材料S11：HomoloGene原始数据，检索日期为2023年2月5日。
Dobrynin, P., Zeng, Y., Norkina, M., Fedorova, A., Zhuk, A., Grigorenko, E. L. (2025). 特定阅读障碍遗传基础的四十年研究历程. 《言语、语言与听力研究杂志》, 68(11), 5158–5173. https://doi.org/10.1044/2025_JSLHR-25-00050