Genetics of Language Disorders

Developmental language disorders with heterologous and overlapping phenotypes and etiologies harbor both complex genetic and environmental influences. Analysis of the genetic elements and the associated phenotypic manifestations in heritable speech and language disorders including developmental verbal dyspraxia (childhood apraxia of speech), specific language impairment, stuttering, dyslexia and speech and sound disorder have revealed multiple genomic regions, quantitative trait loci, epigenetic regulators and transcriptional regulatory and co-regulatory genes with distinct core phenotypes. These analyses have also identified the contribution of genetic determinants to neuronal migration, axon guidance, brain networks, connectivity and lateralization and lysosomal functions that together with environmental modifier effects contribute to speech and language ability. A synthesis from these rich datasets allows additional conclusions that highlight the significant genetic and phenotypic overlaps among speech and language disorders. Collectively, heterogenous genomic pathways and variations in the genetic mechanisms that shape the neuronal architecture lead to neurodevelopmental features and a spectrum in speech and language ability ranging from normality to impairment, consistent with a continuous distribution of multifactorial genetic and environmental causes and a broad heritable verbal trait deficiency underlying developmental speech and language disorders. Key Concepts: Developmental speech and language disorders including verbal dyspraxia, specific language impairment, stuttering, dyslexia and speech and sound disorder are associated with multiple genetic determinants. Language-associated genetic factors contribute to various molecular, cellular and regulatory processes that shape the neuronal architecture through neuron migration, axon guidance, development of brain networks and connectivity and determine neurodevelopmental features. CAS is prominently linked to aberrant functions of FOXP2 and FOXP1 with both overlapping and distinct cognitive and language phenotypes. FOXP2 functional deficiency affects both expressive and receptive language with a core feature of abnormal articulation whereas FOXP1 more significantly contributes to global cognitive impairments that include more severely affected expressive language. In SLI, several quantitative trait loci have been identified and altered functions of genes ATP2C2 and CMIP that contribute to short-term memory performance, KIAA0319 an epigenetic regulator and CNTNAP2 with increased susceptibility to SLI and involvement in early language acquisition. In stuttering, in addition to the involvement of the FOXP2–CNTNAP2 pathways, alterations in intracellular lysosomal functions play a major role. The dyslexia phenotype has been linked to variants of the co-regulatory genes DYX1C1, DCDC2, KIAA0319 and ROBO1 that affect neuronal migration and axon guidance with additional candidate genes CMIP, MC5R, DYM, NEDD4L and DGK1. In SSD, linkage analysis of phonological memory and decoding traits identified regions on chromosomes 3, 1, 6, 15 while genome-wide linkage of the familiar subtype on 8q, 6p and 7q. Candidate genes include ELP4, PAX6 and FOXP2. Significant genetic and phenotypic overlaps exist among developmental speech and language disorders that highlight an underlying broad heritable verbal trait deficiency. A spectrum of variations in speech and language ability is consistent with a continuous distribution of multifactorial genetic and environmental causes. Keywords: language disorders; genetics; SLI; verbal dyspraxia; stuttering; dyslexia; speech and sound disorder; genotype–phenotype correlation