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

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, 100–102]

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, 117–120]; 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 [86–88]

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 [89–91], 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, [133–135]), 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 [64–66]

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