Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Simon Fischer, Faraneh Vargha-Khadem, Kate E. Watkins, Anthony P. Monaco & Marcus E. Pembry Nature Genet 18, 168–170 (1998). Due to a printing error, the text on Table 1, printed here in full, was obscured. We regret this error. Table 1 · Pairwise lod scores for linkage of SPCH1 to 7q markers Recombination fractions (θ) Locus Dist (cM) 0. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed struc- tural abnormalities in several of these same areas, particu- larly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study (Fisher, S., Vargha- Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170) localized the abnormal gene (SPCH1) to a 5.6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family. <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> The KE family is a large three-generational pedigree in which half of the members suffer from a verbal and orofacial dyspraxia in association with a point mutation in the FOXP2 gene. This report extends previous voxel-based morphometric analyses of magnetic resonance imaging (MRI) scans (Watkins et al. [2002] Brain 125:465-478) using a bilateral conjunction analysis. This searches specifically for areas of grey matter density that differ bilaterally in the affected members compared with both matched controls and the unaffected family members. 3-D T1-weighted MRI datasets of 17 family members (10 affected, 7 unaffected) and matched controls were compared. The most significant findings were reduced grey matter density bilaterally in the caudate nucleus, the cerebellum, and the left and right inferior frontal gyrus in the affected members. In addition, increased grey matter density was found bilaterally in the planum temporale. These results confirm that a point mutation in FOXP2 is associated with several bilateral grey matter abnormalities in both motor and language related regions. The results also demonstrate the advantages of using a conjunction analysis when bilateral abnormalities are suspected. <s> BIB005 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language. <s> BIB006 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Specific language impairment (SLI) is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. This condition is highly heritable and affects between 5% and 8% of pre-school children. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. So far, variants in four specific genes have been associated with spoken language disorders - forkhead box P2 (FOXP2) and contactin-associated protein-like 2 (CNTNAP2) on chromosome7 and calcium-transporting ATPase 2C2 (ATP2C2) and c-MAF inducing protein (CMIP) on chromosome 16. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition. <s> BIB007 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Correction to: European Journal of Human Genetics (2012) 20, 224–229; doi:10.1038/ejhg.2011.160; published online 7 September 2011 The authors would like to make the following amendments: The following sentence in the Materials and Methods section: ‘Furthermore, we genotyped the mutation R553H, previously found in a large Pakistani family with severe speech and language disorder’ should read: ‘Furthermore, we genotyped the mutation R553H, previously found in a large English Caucasian family with severe speech and language disorder. <s> BIB008 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | FOXP2 <s> Language-based Learning Disabilities (LLDs) encompass a group of complex, comorbid, and developmentally associated deficits in communication. Language impairment and developmental dyslexia (DD) represent the most recognized forms of LLDs. Substantial genetic correlations exist between language and reading (dis)abilities. Common variants in the FOXP2 gene were consistently associated with language- and reading-related neuropsychological and neuroanatomical phenotypes. We tested the effect of a FOXP2 common variant, that is, rs6980093 (A/G), on quantitative measures of language and reading in two independent Italian samples: a population-based cohort of 699 subjects (3-11 years old) and a sample of 572 children with DD (6-18 years old). rs6980093 modulates expressive language in the general population sample, with an effect on fluency scores. In the DD sample, the variant showed an association with the accuracy in the single word reading task. rs6980093 shows distinct genetic models of association in the two cohorts, with a dominant effect of the G allele in the general population sample and heterozygote advantage in the DD cohort. We provide preliminary evidence that rs6980093 associates with language and reading (dis)abilities in two independent Italian cohorts. rs6980093 is an intronic SNP, suggesting that it (or a linked variant) modulates phenotypic association via regulation of FOXP2 expression. Because FOXP2 brain expression is finely regulated, both temporally and spatially, it is possible that the two alleles at rs6980093 differentially modulate expression levels in a developmental stage- or brain area-specific manner. This might help explaining the heterozygote advantage effect and the different genetic models in the two cohorts. <s> BIB009
FOXP2 was first linked to language impairment in the KE family, which gained the attention of geneticists because half of the members are affected by a severe inherited speech and language disorder BIB001 BIB003 . Genetic associations with this speech and language disorder have been extensively investigated in a three-generation pedigree of the KE family that includes 27 family members BIB003 . More recently, FOXP2 has been linked to variability in language and reading traits in both the general population and in a clinical sample BIB009 . Using linkage analyses, researchers first identified the locus associated with inheritance of the disorder (SPCH1, chromosome 7q31), and later determined that a mutation in the gene FOXP2 was causally related to the disorder BIB001 BIB003 . FOXP2 belongs to a family of genes that produce proteins that regulate expression of other genes during neurodevelopmental processes  , leading to complex and widespread contribution of this gene to neurodevelopment BIB007 . Among the series of studies investigating the nature of the KE family's impairment are several examinations of neural structure and function. Studies of gray matter structure in the KE family have revealed atypical gray matter volume and density in affected compared to unaffected family members in cortical and subcortical regions associated with motor and language functions including the inferior frontal gyrus, pre-supplementary motor area, caudate nucleus, and cerebellum BIB005 BIB002 BIB004 . These early findings point toward a relationship of FOXP2 with brain structure in regions related to speech production and language; however, additional studies are needed to confirm whether these patterns hold in members of the general population who exhibit atypical expression of FOXP2. In addition to structural anomalies, affected members of the KE family have shown altered functional neural activation during both overt and covert language production tasks in motor areas and language-related regions BIB006 BIB002 . Research in the KE family has also led to the investigation of functional associations with FOXP2 SNPs in the general population, with consistent findings related to activation in the left inferior frontal cortex  BIB008 . For example, associations have been observed between rs6980093 and left inferior frontal activation and between rs7784315 and rs17137135 and left precentral activation in response to sentences presented in auditory and visual modalities in a study of typically developing young adults  . Moreover, BIB008 included typically developing children and children with SRD in their fMRI study of FOXP2 SNPs. Results revealed decreased activation during a rhyme decision task in the temporo-parietal cortex, inferior frontal cortex, superior occipital gyrus, and lingual gyrus in carriers of the risk allele on rs1253305 BIB008 . This evidence suggests that the neural alterations associated with FOXP2 are not limited to the mutation characteristic of the KE family, but may play a role in language disorders more broadly with possible implications for reading impairment.