On Genes_ Speech_ and Language NEJM by dfgh4bnmu


									PE R S PE C TI V E                                                                             on genes, speech, and language

On Genes, Speech, and Language
Simon E. Fisher, D.Phil.
                                                                                                         Related article, page 1694

           L    earning to talk is one of the
                most important milestones in
           human development, but we still
                                                   clusionary manner (the presence
                                                   of speech or language problems
                                                   that cannot be explained by an
                                                                                              fine motor sequences that under-
                                                                                              lie speech. This large variety of
                                                                                              communication problems is re-
           have only a limited understand-         obvious medical condition) and             flected by diagnostic schemes that
           ing of the way in which the pro-        so encompass a wide variety of             contain several distinct categories
           cess occurs. It normally takes just     phenotypes.1 For example, lin-             (expressive, mixed, phonologic,
           a few years to go from babbling         guistic deficits can be confined           apraxic–dyspraxic, and so on). In
           newborn to fluent communica-            to expressive language or can ex-          practice, there frequently are co-
           tor. During this period, the child      tend to receptive abilities, al-           existing disorders involving vari-
           learns to produce a rich array of       though pure receptive impairment           ous types of impairment, and the
           speech sounds through intricate         is seldom seen. When it comes to           boundaries between these disor-
           control of articulatory muscles,        speech output, affected children           ders can be fluid; a person may
           assembles a vocabulary compris-         may fail to produce sounds that            move from one category to an-
           ing thousands of words, and de-         would be expected on the basis of          other at various stages of life.
           duces the complicated structural        age and dialect, which may be                  Although the causes of these
           rules that permit construction          associated with difficulties in the        kinds of disorders remain large-
           of meaningful sentences. All of         planning and execution of the              ly elusive, familial clustering and
           this (and more) is achieved with
           little conscious effort.
               The acquisition of language
           usually proceeds along robust                                                         21

           lines without any need for explic-                                        15.3
                                                                                                 15.2            p
           it tuition, in stark contrast to oth-                                                 14
           er complex learned abilities, like                                         13
           reading, writing, and mathemat-                                                       12
           ics. However, a small minority of                                         11.1                        Centromere
           children are unable to acquire                                           11.22
                                                                  WBS region
           speech and language proficiency,                                                      11.23
           despite growing up in language-                                           21.1
           rich environments and showing                                             21.3
           adequate performance in other                                                         22              q
           areas, such as hearing and non-                                           31.1
                                                                      FOXP2                      31.2
           verbal cognition. For some of
           these children, early difficulties
           with communication resolve with                                                       32
           age, but for others the problems                                                      34
           continue into adulthood. Since                                                        36
           modern society depends heavily
           on language and literacy skills,
           persistent impairment is often          Chromosome 7 Gene Dosage and Speech and Language Disorder.
           accompanied by wider problems           An ideogram of chromosome 7 shows cytogenetic banding (with two regions of the
           in educational, social, and emo-        long q arm highlighted), a 600-kb region containing the FOXP2 gene, and a 1.5-Mb
                                                   interval that is commonly deleted in the Williams–Beuren syndrome (WBS). Point
           tional development in later life.       mutations and chromosomal abnormalities involving FOXP2 are one cause of develop-
               Developmental communication         mental verbal dyspraxia. Duplication of the WBS region may also be associated with a
           disorders are diagnosed in an ex-       delay in speech.

                                            n engl j med 353;16    www.nejm.org   october 20, 2005                               1655
PE R S PE C T IV E                                                                             on genes, speech, and language

           twin-based heritability studies         been hypothesized that reduced            the consequences of deletion and
           provide strong evidence of ge-          amounts of functional FOXP2               duplication of this same interval
           netic influences.1 At the same          protein yield subtle anomalies            appear to be strikingly different,
           time, it is clear that the observed     in neural organization that im-           at least with respect to speech
           phenotypic heterogeneity is un-         pair speech and language acqui-           articulation and expressive lan-
           derpinned by a mixture of ge-           sition.                                   guage. Third, the present report
           netic effects, which range from             A report in this issue of the         concerns only a single case, but
           common risk alleles acting in a         Journal (pages 1694–1701) presents        the investigators speculate that
           multifactorial framework to rare        evidence that alteration in dosage        duplication of the region could
           instances of highly penetrant           of genes elsewhere on the long            occur at a frequency similar to
           point mutations behaving in a           arm of chromosome 7 may be                that of the common WBS dele-
           classic mendelian fashion.2 The         another cause of speech and lan-          tion, since it is mediated by a
           dissection of such a complicated        guage disturbances. Previously,           related mechanism of interchro-
           state of affairs calls on geneticists   studies of a rare cytogenetic ab-         mosomal recombination, involv-
           to use multiple complementary           normality known as supernumer-            ing flanking low-copy-number
           strategies of both a traditional        ary ring chromosome 7 indicated           repeats. As such, 7q11.23 dupli-
           and a novel nature. By adopting         that large duplications of 7q are         cations may contribute to the in-
           a variety of approaches, linkage        associated with severely retarded         cidence of unexplained deficits in
           studies of prevalent types of           speech development.5 In the cur-          speech and language in human
           speech and language disorders           rent study, Somerville and col-           populations.
           have implicated several regions of      leagues have identified a boy with            The duplicated region in this
           the genome, most notably on             childhood apraxia of speech ac-           case contains as many as 27
           chromosomes 3, 13, 16, and 19.          companied by dramatic disrup-             genes, and it is unclear which of
           The putative risk genes underly-        tion of expressive language, a            these genes are relevant to the
           ing these linkages have yet to be       disorder that appears to be               disorder. Somerville et al. dem-
           identified, but progress is en-         caused by a 1.5-Mb duplication            onstrate increased expression of
           couraging.                              of 7q11.23.                               several of the duplicated genes
               In the case of a rare domi-             These findings are intriguing         in lymphoblastoid cells, but re-
           nant mendelian form of impair-          on a number of counts. First, they        lating this sort of finding to neu-
           ment, it has been possible to go        add support to the hypothesis             rodevelopment could be difficult,
           even further and home in on a           that the development of neural            particularly since neural tissue
           specific gene, known as FOXP2,          circuitry involved in speech and          may tolerate changes in dosage
           located in chromosomal band             language acquisition can be high-         of some genes but not others.
           7q31 (see diagram). People who          ly sensitive to gene copy num-            Moreover, the genes whose in-
           carry heterozygous disruption of        ber. Although FOXP2-related dis-          creased dosage leads to language
           this gene have problems sequenc-        order has thus far been linked            disruption in the child carrying
           ing the precise movements of            to reduced functional dosage, the         the duplication may not neces-
           tongue, lips, jaw, and palate that      present study shows that increased        sarily be the same as the genes
           contribute to intelligible speech       levels of transcription of one or         that yield an uneven linguistic
           (known as verbal dyspraxia or           more genes may also be an im-             profile in WBS. A proper under-
           childhood apraxia of speech).3,4        portant mechanism accounting              standing of genotype–phenotype
           They also have difficulties with        for cases of speech and language          relationships will require exten-
           learning and production of non-         disorder. Second, the duplicated          sive future study and may de-
           speech sequences involving the          interval of 7q11.23 corresponds           pend on discovery of partial du-
           orofacial musculature (orofacial        directly with the region most             plications of the common WBS
           dyspraxia) and have a broad pro-        commonly deleted in the Wil-              region, as well as investigation
           file of linguistic deficits in ex-      liams–Beuren syndrome (WBS),              of 7q11.23 gene polymorphism
           pressive and receptive domains          a neurodevelopmental disorder in          in cohorts of children with speech
           — problems that affect both             which language tends to be an             and language disorders, particu-
           oral and written language. It has       area of relative strength. Thus,          larly those with speech apraxia.

1656                                        n engl j med 353;16   www.nejm.org   october 20, 2005
PE R S PE C TI V E                                                                                  on genes, speech, and language

              We are just starting to unrav-       bination with findings from                      2. Fisher SE, Lai CSL, Monaco AP.
                                                                                                    Deciphering the genetic basis of speech and
           el the genetic causes of develop-       other disciplines, such as neuro-                language disorders. Annu Rev Neurosci
           mental communication disorders          imaging and developmental psy-                   2003;26:57-80.
           and explore how they relate to          chology, hold promise for shed-                  3. Vargha-Khadem F, Gadian DG, Copp A,
                                                                                                    Mishkin M. FOXP2 and the neuroanatomy of
           language problems in other neu-         ding light on the mechanisms by                  speech and language. Nat Rev Neurosci
           rodevelopmental syndromes, such         which speech and language ac-                    2005;6:131-8.
           as autism and dyslexia. Success         quisition can go awry.                           4. MacDermot KD, Bonora E, Sykes N, et al.
                                                                                                    Identification of FOXP2 truncation as a novel
           in this area raises the possibility                                                      cause of developmental speech and lan-
                                                   Dr. Fisher is a Royal Society Research Fellow
           of using molecular diagnostics          at the Wellcome Trust Centre for Human Ge-       guage deficits. Am J Hum Genet
           for early identification of children    netics, University of Oxford, Oxford, England.   2005;76:1074-80.
                                                                                                    5. Lichtenbelt KD, Hochstenbach R, van
           who are at increased risk, thus                                                          Dam WM, Eleveld MJ, Poot M, Beemer FA.
           enabling environmental interven-        1. Bishop DVM. Genetic and environmental         Supernumerary ring chromosome 7 mosa-
                                                   risks for specific language impairment in        icism: case report, investigation of the gene
           tions to begin at a younger age.        children. Philos Trans R Soc Lond B Biol Sci     content, and delineation of the phenotype.
           Overall, genetic studies, in com-       2001;356:369-80.                                 Am J Med Genet A 2005;132:93-100.

                                            n engl j med 353;16   www.nejm.org       october 20, 2005                                     1657

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