Alternative titles; symbols
SNOMEDCT: 229703009; ORPHA: 209908; DO: 0111275;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q31.1 | Speech-language disorder-1 | 602081 | Autosomal dominant | 3 | FOXP2 | 605317 |
A number sign (#) is used with this entry because of evidence that this form of speech and language abnormality (SPCH1) is caused by heterozygous mutation in the FOXP2 gene (605317) on chromosome 7q31.
Speech-language disorder-1 is an autosomal dominant disorder characterized by severe orofacial dyspraxia resulting in largely incomprehensible speech. Affected individuals were originally thought to have specific defects in the use of grammatical suffixation rules (Gopnik, 1990; Gopnik and Crago, 1991). The phenotype, however, is broader in nature, with virtually every aspect of grammar and language affected (Fisher et al., 1998). Vargha-Khadem et al. (1998) concluded that the disorder is characterized by abnormal development of several brain areas critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language.
Relation to Specific Language Impairment
Children who fail to develop expressive and/or receptive language normally, in the absence of explanatory factors such as neurologic disorders, hearing impairment, or lack of adequate opportunity, are clinically described as having specific language impairment (SLI; see 606711) (Bartlett et al., 2002).
See also familial developmental dysphasia (600117).
Hurst et al. (1990) reported a family, identified as 'KE,' in which 16 members spanning 3 generations had a severe developmental verbal dyspraxia with normal hearing and intelligence. Inheritance was autosomal dominant. Vargha-Khadem et al. (1995) restudied the 'KE' family, and noted that about half of the male and female members of 4 generations suffered from the severe speech and language disorder. Gopnik (1990) and Gopnik and Crago (1991) reported findings suggesting that the affected members suffered from a specific impairment in grammar, namely, a selective inability to generate syntactic rules such as those for tense, number, and gender. Reported selectivity of the impairment led Gopnik (1990) and Gopnik and Crago (1991), as well as Pinker (1991, 1994) and Jackendoff (1994), to conclude that the KE family has an inherited grammar-specific disorder and thus provides evidence for the existence of 'grammar genes.' However, Vargha-Khadem et al. (1995) described investigations of the same family indicating that the affected members' disorder transcends the generation of morphosyntactic rules to include impaired processing and expression of other areas of grammar, grossly defective articulation of speech sounds, and a severe extralinguistic orofacial dyspraxia. The dyspraxia rendered their speech largely incomprehensible to the naive listener. In addition, the affected family members had both verbal and performance IQ scores that were on average 18 to 19 points below those of the unaffected members. This psychologic profile indicated that the inherited disorder does not affect morphosyntax exclusively, or even primarily; rather, it affects intellectual, linguistic, and orofacial praxic functions generally.
Fisher et al. (1998) gave preliminary reports on brain imaging studies of affected and unaffected members of the KE pedigree. Findings suggested that the mutation at the SPCH1 locus results in functional abnormalities in motor-related areas of the frontal lobe, and that these are due, in turn, to abnormal anatomical development of several brain areas, with a key cytopathology being located in the neostriatum. Fisher et al. (1998) suggested that analysis of the gene could further understanding of both the structure and the function of the frontoneostriatal system.
Extensive studies of the neural basis of the disorder in the KE family were reported by Vargha-Khadem et al. (1998). The core deficit responsible for the verbal dyspraxia involved 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 structural abnormalities in several of the same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. The authors concluded that genetic mutation or deletion of the SPCH1 gene resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language.
Watkins et al. (1999) reviewed studies of brain morphometry and function in developmental language disorders and described studies of the autosomal dominant trait in the KE family. Studies of brain morphometry were stimulated by the landmark study of Geschwind and Levitsky (1968), which provided evidence of asymmetry in brain structure that correlated with the well-established functional asymmetry and dominance of the left hemisphere for language. By autopsy of 100 normal brains, they found that the planum temporale (which falls within Wernicke's area, known to be associated with language disorders when damaged in adulthood) was longer on the left in 65%, symmetric in 25%, and shorter on the left in 10% of the sample. This pattern has been found not only in adults but also in fetuses and neonates. Galaburda et al. (1978) showed that the gross asymmetry was associated with microscopic cytoarchitectonic differences between the hemispheres. Watkins et al. (1999) stated that half the members of the first 3 generations of the KE family were affected by a severe disorder of speech and language, which often made their speech unintelligible. The fourth-generation children were all born to unaffected parents and did not demonstrate the disorder; the affected family members of the third generation did not have children. Although no instance of male-to-male transmission was noted, the involvement of 9 females and 6 males suggested that the disorder is not X-linked. It was in this family that linkage to 7q31 was demonstrated for the locus, designated SPCH1. On the basis of their findings with imaging methods, Watkins et al. (1999) suggested that the genetic abnormality in the KE family may directly and selectively affect the development of the caudate nucleus or, perhaps, that of the basal ganglia more generally, resulting in both structural and functional abnormalities of the caudate nuclei bilaterally.
Liegeois et al. (2003) performed functional MRI (fMRI) language experiments on several members of the KE family. During covert (silent) verb generation and overt (spoken) verb generation and word repetition, 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 morphologic abnormalities, the affected members showed significant underactivation relative to unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. The findings suggested that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.
MacDermot et al. (2005) reported a 4-year-old boy with developmental delay in speech, language, and social skills. He communicated mainly using single words and was unable to repeat multisyllabic words. His 20-month-old sister had a history of motor and oropharyngeal dyspraxia, was unable to speak any words, could not identify objects, and had poor vocalization. Their mother reported a history of speech delay in childhood and showed severe problems in communication, with poor speech clarity and simple grammatical construction. All 3 patients were found to have a heterozygous nonsense mutation in the FOXP2 gene (605317.0002).
Fisher et al. (1998) noted the report of an interstitial deletion involving 7q31 by Sarda et al. (1988). A 7-year-old boy presented with a dysmorphic face and absence of speech, despite language comprehension and psychomotor development equivalent to those of a 5-year-old. The deletion involved 7q31.2-q32.3.
Tyson et al. (2004) described a 14-year-old boy with a cryptic interstitial 7q31.3 deletion who presented with bilateral cleft lip and palate, hearing loss, mild mental retardation, and a language processing disorder. Chromosomal comparative genomic hybridization (CGH) studies of the patient proved inconclusive. Array CGH analysis, which was initiated to perform a higher resolution search for gains and losses, revealed deletion of 2 adjacent clones that map to 7q31.3 and are 4.4 Mb apart. The deletion was confirmed by FISH.
Zeesman et al. (2006) reported a 5-year-old girl with an interstitial deletion of paternally-derived chromosome 7q31.2-q32.2 encompassing the FOXP2 gene. She had a severe communication disorder with evidence of oromotor dyspraxia and mild developmental delay. She was unable to cough, sneeze, or laugh spontaneously. She also had dysmorphic features, including microcephaly, brachycephaly, small nose, long philtrum, and downturned corners of the mouth.
Rice et al. (2012) reported a mother and son with FOXP2 haploinsufficiency due to a 1.57-Mb deletion on chromosome 7q31, which included 2 other genes, MDFIC (614511) and PPP1R3A (600917). The boy had severe childhood apraxia of speech, with poor expressive speech, severely delayed speech acquisition, and inability to laugh, sneeze or cough spontaneously. He showed mildly impaired cognition, which may have been due to the speech limitations. He also lacked fine motor control. His 24-year-old mother was similarly, if slightly less, affected. She had a similar early developmental history, with speech apraxia and mild developmental delay. Neither patient had autistic features.
Zilina et al. (2012) reported 2 unrelated families with speech and language disorders and other neurologic deficits associated with deletions of chromosome 7q31 involving the FOXP2 gene. A mother and daughter in the first family were affected. Both had problems chewing and swallowing food, showed pronounced drooling, and had delayed onset of the cough reflex in early life, as well as an inability to sneeze. The daughter showed failure to thrive, developmental delay, dysmorphic features, nystagmus, and myopia. Brain MRI showed mild brain atrophy and mild white matter hyperintensities. At age 3 years, she had some autistic features, low vocalization, poor vocabulary, and mild hand tremor. The mother had some autistic features, moderate speech delay, below average intelligence (IQ 88), poor social skills, emotional lability, and developmental verbal dyspraxia with difficulty in speech expression. Microarray analysis identified an 8.3-Mb deletion on chromosome 7q31.1-q31.31 including the FOXP2 gene in both the mother and the daughter. The mother's deletion was on the paternally derived chromosome. In the second family, the proband had developmental delay, mild dysmorphic features, mild ataxia, occasional aggressive behavior, and significant pronunciation difficulties with poor vocabulary. Her mother had intellectual disability, aggressive behavior, and developmental verbal dyspraxia. The maternal aunt of the proband had a phenotype similar to that of the mother. The maternal grandfather completed only 4 grades at school, had a severe speech defect, aggressive behavior, and balance problems. Molecular analysis in this family showed that the proband, the maternal aunt, and the maternal grandfather all carried a 6.5-Mb deletion of 7q31 including the FOXP2 gene; the mother of the proband refused study. The findings suggested no significant phenotypic difference due to parental origin of FOXP2 defects.
By a genomewide linkage search, Fisher et al. (1997, 1998) identified a region on chromosome 7 that cosegregated with the speech and language disorder (maximum lod score = 6.62), confirming autosomal dominant inheritance with full penetrance. Fine mapping with all available microsatellites from the region enabled them to localize the gene (designated SPCH1) to a 5.6-cM interval in 7q31.
Lai et al. (2000) used bioinformatic analyses to assemble a detailed BAC/PAC-based sequence map of the interval on 7q31 shown to contain the SPCH1 gene. The region was found to contain 152 STSs, 20 known genes, and more than 7.75 Mb of completed genomic sequence. They screened the affected chromosome 7 from the KE family with 120 of these STSs, but could detect no evidence of microdeletion. Novel polymorphic markers were generated from the sequence and were used to localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between 2 markers containing approximately 6.1 Mb of completed sequence. In addition, Lai et al. (2000) studied 2 unrelated patients with a similar speech and language disorder, who had de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient to a single clone within the newly refined SPCH1 interval. This clone contained the CAGH44 gene (605317), which encodes a brain-expressed protein containing a large polyglutamine stretch. However, Lai et al. (2000) found the t(2;7)(q23;q31.3) breakpoint in the second patient resided within a BAC clone mapping more than 3.7 Mb distal to CAGH44, outside of the SPCH1 critical region. Finally, they investigated the CAGH44 gene in affected individuals of the KE family, and found no mutations in the then-known coding sequence.
Lai et al. (2001) demonstrated that the FOXP2 gene, which encodes a putative transcription factor containing a polyglutamine tract and forkhead DNA-binding domain, is directly disrupted in the translocation breakpoint in patient CS (unrelated to the family KE). This patient, initially reported by Lai et al. (2000), had speech and language impairment associated with the chromosomal translocation involving the SPCH1 interval. Lai et al. (2001) also identified a point mutation affecting members of the KE family that alters an invariant amino acid residue in the forkhead domain (605317.0001).
In 1 of 49 probands with a specific diagnosis of verbal dyspraxia, MacDermot et al. (2005) identified a heterozygous mutation in the FOXP2 gene (605317.0002). The proband's sister and mother also had the mutation.
Shu et al. (2005) found that Foxp2-null mice demonstrated severe motor abnormalities, premature death, and an absence of ultrasonic vocalizations that are usually elicited when pups are removed from their mothers. Foxp2 +/- mice showed modest developmental motor delays but significant decreases in the number of ultrasonic vocalizations. However, the duration, peak frequency, and bandwidth of the vocalizations were indistinguishable from wildtype. Neuropathologic examination showed severely abnormal early development of cerebellar neuronal cell layers in knockout mice, with less severe changes in heterozygous mice.
Folstein and Mankoski (2000) suggested a relationship between autism (see 209850) and SPCH1 or specific language impairment because genetic studies in the disorders pointed to a locus on 7q31 (see AUTS9, 611015). However, Newbury et al. (2002), using association and mutation screening analyses, concluded that the coding region variants in FOXP2 do not underlie the AUTS9 linkage, and that the FOXP2 gene is unlikely to play a role in autism or more common forms of language impairment.
Bartlett, C. W., Flax, J. F., Logue, M. W., Vieland, V. J., Bassett, A. S., Tallal, P., Brzustowicz, L. M. A major susceptibility locus for specific language impairment is located on 13q21. Am. J. Hum. Genet. 71: 45-55, 2002. [PubMed: 12048648] [Full Text: https://doi.org/10.1086/341095]
Fisher, S. E., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P., Pembrey, M. E. Localisation of a gene implicated in a severe speech and language disorder. Nature Genet. 18: 168-170, 1998. Note: Erratum: Nature Genet. 18: 298 only, 1998. [PubMed: 9462748] [Full Text: https://doi.org/10.1038/ng0298-168]
Fisher, S. E., Vargha-Khadem, F., Watkins, K., Monaco, A. P., Pembrey, M. Localisation of a gene implicated in a severe speech and language disorder. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A28 only, 1997.
Folstein, S. E., Mankoski, R. E. Chromosome 7q: where autism meets language disorder? (Editorial) Am. J. Hum. Genet. 67: 278-281, 2000. [PubMed: 10889044] [Full Text: https://doi.org/10.1086/303034]
Galaburda, A. M., Sanides, F., Geschwind, N. Human brain: cytoarchitectonic left-right asymmetries in the temporal speech region. Arch. Neurol. 35: 812-817, 1978. [PubMed: 718483] [Full Text: https://doi.org/10.1001/archneur.1978.00500360036007]
Geschwind, N., Levitsky, W. Human brain: left-right asymmetries in temporal speech region. Science 161: 186-187, 1968. [PubMed: 5657070] [Full Text: https://doi.org/10.1126/science.161.3837.186]
Gopnik, M., Crago, M. B. Familial aggregation of a developmental language disorder. Cognition 39: 1-50, 1991. [PubMed: 1934976] [Full Text: https://doi.org/10.1016/0010-0277(91)90058-c]
Gopnik, M. Feature-blind grammar and dysphasia. (Letter) Nature 344: 715, 1990. [PubMed: 2330028] [Full Text: https://doi.org/10.1038/344715a0]
Hurst, J. A., Baraitser, M., Auger, E., Graham, F., Norel, S. V. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 32: 352-355, 1990. [PubMed: 2332125] [Full Text: https://doi.org/10.1111/j.1469-8749.1990.tb16948.x]
Jackendoff, R. Patterns in the Mind: Language and Human Nature. New York: Basic Books (pub.) 1994.
Lai, C. S. L., Fisher, S. E., Hurst, J. A., Levy, E. R., Hodgson, S., Fox, M., Jeremiah, S., Povey, S., Jamison, D. C., Green, E. D., Vargha-Khadem, F., Monaco, A. P. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am. J. Hum. Genet. 67: 357-368, 2000. [PubMed: 10880297] [Full Text: https://doi.org/10.1086/303011]
Lai, C. S. L., Fisher, S. E., Hurst, J. A., Vargha-Khadem, F., Monaco, A. P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413: 519-523, 2001. [PubMed: 11586359] [Full Text: https://doi.org/10.1038/35097076]
Liegeois, F., Baldeweg, T., Connelly, A., Gadian, D. G., Mishkin, M., Vargha-Khadem, F. Language fMRI abnormalities associated with FOXP2 gene mutation. Nature Neurosci. 6: 1230-1237, 2003. [PubMed: 14555953] [Full Text: https://doi.org/10.1038/nn1138]
MacDermot, K. D., Bonora, E., Sykes, N., Coupe, A.-M., Lai, C. S. L., Vernes, S. C., Vargha-Khadem, F., McKenzie, F., Smith, R. L., Monaco, A. P., Fisher, S. E. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am. J. Hum. Genet. 76: 1074-1080, 2005. [PubMed: 15877281] [Full Text: https://doi.org/10.1086/430841]
Newbury, D. F., Bonora, E., Lamb, J. A., Fisher, S. E., Lai, C. S. L., Baird, G., Jannoun, L., Slonims, V., Stott, C. M., Merricks, M. J., Bolton, P. F., Bailey, A. J., Monaco, A. P., International Molecular Genetic Study of Autism Consortium. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am. J. Hum. Genet. 70: 1318-1327, 2002. [PubMed: 11894222] [Full Text: https://doi.org/10.1086/339931]
Pinker, S. Rules of language. Science 253: 530-535, 1991. [PubMed: 1857983] [Full Text: https://doi.org/10.1126/science.1857983]
Pinker, S. The Language Instinct. New York: William Morrow and Company, Inc. (pub.) 1994.
Rice, G. M., Raca, G., Jakielski, K. J., Laffin, J. J., Iyama-Kurtycz, C. M., Hartley, S. L., Sprague, R. E., Heintzelman, A. T., Shriberg, L. D. Phenotype of FOXP2 haploinsufficiency in a mother and son. Am. J. Med. Genet. 158A: 174-181, 2012. [PubMed: 22106036] [Full Text: https://doi.org/10.1002/ajmg.a.34354]
Sarda, P., Turleau, C., Cabanis, M.-O., Jalaguier, J., de Grouchy, J., Bonnet, H. Deletion interstitielle du bras long du chromosome 7. Ann. Genet. 31: 258-261, 1988. [PubMed: 3265313]
Shu, W., Cho, J. Y., Jiang, Y., Zhang, M., Weisz, D., Elder, G. A., Schmeidler, J., De Gasperi, R., Gama Sosa, M. A., Rabidou, D., Santucci, A. C., Perl, D., Morrisey, E., Buxbaum, J. D. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc. Nat. Acad. Sci. 102: 9643-9648, 2005. [PubMed: 15983371] [Full Text: https://doi.org/10.1073/pnas.0503739102]
Tyson, C., McGillivray, B., Chijiwa, C., Rajcan-Separovic, E. Elucidation of a cryptic interstitial 7q31.3 deletion in a patient with a language disorder and mild mental retardation by array-CGH. Am. J. Med. Genet. 129A: 254-260, 2004. [PubMed: 15326624] [Full Text: https://doi.org/10.1002/ajmg.a.30245]
Vargha-Khadem, F., Watkins, K., Alcock, K., Fletcher, P., Passingham, R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc. Nat. Acad. Sci. 92: 930-933, 1995. [PubMed: 7846081] [Full Text: https://doi.org/10.1073/pnas.92.3.930]
Vargha-Khadem, F., Watkins, K. E., Price, C. J., Ashburner, J., Alcock, K. J., Connelly, A., Frackowiak, R. S. J., Friston, K. J., Pembrey, M. E., Mishkin, M., Gadian, D. G., Passingham, R. E. Neural basis of an inherited speech and language disorder. Proc. Nat. Acad. Sci. 95: 12695-12700, 1998. [PubMed: 9770548] [Full Text: https://doi.org/10.1073/pnas.95.21.12695]
Watkins, K. E., Gadian, D. G., Vargha-Khadem, F. Functional and structural brain abnormalities associated with a genetic disorder of speech and language. Am. J. Hum. Genet. 65: 1215-1221, 1999. [PubMed: 10521285] [Full Text: https://doi.org/10.1086/302631]
Zeesman, S., Nowaczyk, M. J. M., Teshima, I., Roberts, W., Cardy, J. O., Brian, J., Senman, L., Feuk, L., Osborne, L. R., Scherer, S. W. Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am. J. Med. Genet. 140A: 509-514, 2006. [PubMed: 16470794] [Full Text: https://doi.org/10.1002/ajmg.a.31110]
Zilina, O., Reimand, T., Zjablovskaja, P., Mannik, K., Mannamaa, M., Traat, A., Puusepp-Benazzouz, H., Kurg, A., Ounap, K. Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families. Am. J. Med. Genet. 158A: 254-256, 2012. [PubMed: 22105961] [Full Text: https://doi.org/10.1002/ajmg.a.34378]