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Table 1 Neurogenomics of speech and language: summary of key genes discussed in the article

From: Neurogenomics of speech and language disorders: the road ahead

Chromosome region Candidate gene Protein function Neurodevelopmental disorders Functional studies of specific risk variants
3p14 FOXP1 Forkhead-box transcriptional repressor [78]; can form heterodimers with FOXP2 protein Rare point mutations, deletions and translocations reported in intellectual disability (ID) and autism spectrum disorder (ASD), accompanied by severe speech and language problems [68, 100102] Cell-based analyses support a two-hit mechanism in a severely affected ASD case with two rare coding mutations; one in FOXP1, the other in CNTNAP2, disturbing a shared functional pathway [68]; reporter gene assays described for another FOXP1 variant, implicated in ID and ASD [100]
7q31 FOXP2 Forkhead-box transcriptional repressor [77]; can form heterodimers with FOXP1 protein Rare point mutations, deletions and translocations reported in families and cases of developmental verbal dyspraxia (DVD)/childhood apraxia of speech (CAS) [17, 22, 24] Known etiological point mutations disrupt function in cellular models [77, 83, 84] and mutant mice [82, 117120]; the latter studies suggested effects of risk variants on neurite outgrowth [82], neural plasticity and acquisition of motor skills [117, 118], and auditory-motor association learning [120]
7q35 CNTNAP2 Transmembrane scaffolding protein; member of neurexin superfamily; clusters K+ channels at nodes of Ranvier; implicated in neuronal migration, dendritic arborization and spine development [8688] Homozygous loss-of-function mutations cause cortical dysplasia with focal epilepsy [88]; common non-coding variants associated with various neuro-developmental disorders, for example, ASD [8991], specific language impairment (SLI) [44], selective mutism [93]; also reports of links to schizophrenia [92] and Tourette syndrome [94] Coding variants identified in ASD show impaired cellular trafficking [140]; neuroimaging genetics has suggested that common non-coding risk alleles have effects on brain structure/function in the general population (for example, [133135]), although sample sizes were small and findings have been inconsistent between studies
12p13 ELKS/ERC1 Member of family of RIM-binding proteins; RIMs are active zone proteins that regulate neurotransmitter release [27] Rare deletions reported in cases of DVD/CAS [26] None reported to date
12q23 GNPTAB Alpha and beta subunits of GlcNAc-phosphotransferase; catalyzes addition of mannose 6-phosphate tag to hydrolytic enzymes, allowing lysosomal targeting Rare coding variants reported in cases of persistent stuttering [57] None reported to date
16p13 GNPTG Gamma subunits of GlcNAc-phosphotransferase (see above) Rare coding variants reported in cases of persistent stuttering [57] None reported to date
16p13 NAGPA 'Uncovering enzyme'; catalyzes second step in tagging hydrolytic enzymes for lysosomal targeting [103] Rare coding variants reported in cases of persistent stuttering [57] Coding mutations found to affect enzymatic activity, protein folding and proteasomal degradation in cell-based assays [103]
16q23 CMIP Cytoskeletal adaptor protein; interacts with filamin A and RelA [43] Common non-coding variants associated with non-word repetition deficits in families with SLI [41] None reported to date
16q24 ATP2C2 Integral membrane P-type ATPase; catalyzes Ca2+/Mn2+ transport into Golgi lumen [42] Common non-coding variants associated with non-word repetition deficits in families with SLI [41] None reported to date
18q12 SETBP1 Interacts with SET, an oncogene involved in DNA replication [6466] Haploinsufficiency reported in cases of expressive speech/language impairment (for example, [65]); dominant gain-of-function point mutations cause a distinct reproductively lethal disorder, Schinzel-Giedion syndrome [64] None reported to date