New Genes for Focal Epilepsies with Speech and Language Disorders

  • Samantha J. Turner
  • Angela T. Morgan
  • Eliane Roulet Perez
  • Ingrid E. Scheffer
Genetics (V Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics


The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-d-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20 % of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.


Epilepsy-aphasia spectrum Speech Language Gene Landau-Kleffner syndrome Epileptic encephalopathy with continuous spike-wave during sleep Benign childhood epilepsy with centro-temporal spikes GRIN2A RBFOX genes Copy number variants Dysarthria Speech dyspraxia Oromotor dyspraxia Continuous spike-wave in slow sleep Rolandic Atypical benign partial epilepsy Autosomal dominant rolandic epilepsy with speech dyspraxia 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7:523–30.PubMedGoogle Scholar
  2. 2.
    Tsai MH, Vears DF, Turner SJ, et al. Clinical genetic study of the epilepsy-aphasia spectrum. Epilepsia. 2013;54:280–7.PubMedGoogle Scholar
  3. 3.
    Deonna T, Roulet-Perez E. Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and regressive autistic disorders with epileptic EEG abnormalities: the continuing debate. Brain Dev. 2010;32:746–52.PubMedGoogle Scholar
  4. 4.
    Rudolf G, Valenti MP, Hirsch E, Szepetowski P. From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors. Epilepsia. 2009;50 Suppl 7:25–8.PubMedGoogle Scholar
  5. 5.
    Tassinari CA, Cantalupo G, Dalla Bernardina B, et al. Encephalopathy related to status epilepticus during slow sleep (ESES) including Landau-Kleffner syndrome. In: Bureau M, Genton P, Dravet C, Delgado-Escueta A, Tassinari CA, Thomas P, et al., editors. Epileptic syndromes in infancy, childhood and adolescence. 5th ed. London: John Libbey Eurotext; 2012. p. 255–75.Google Scholar
  6. 6.
    Roulet Perez E, Davidoff V, Despland PA, Deonna T. Mental and behavioural deterioration of children with epilepsy and CSWS: acquired epileptic frontal syndrome. Dev Med Child Neurol. 1993;35:661–74.PubMedGoogle Scholar
  7. 7.
    Tassinari CA, Bureau M, Dravet C, Roger J, Daniele-Natale O. Electrical status epilepticus during sleep in children (ESES). In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy. New York: Academic; 1982. p. 465–79.Google Scholar
  8. 8.
    Deonna TW, Roulet E, Fontan D, Marcoz JP. Speech and oromotor deficits of epileptic origin in benign partial epilepsy of childhood with rolandic spikes (BPERS). Relationship to the acquired aphasia-epilepsy syndrome. Neuropediatrics. 1993;24:83–7.PubMedGoogle Scholar
  9. 9.
    Roulet E, Deonna T, Despland PA. Prolonged intermittent drooling and oromotor dyspraxia in benign childhood epilepsy with centrotemporal spikes. Epilepsia. 1989;30:564–8.PubMedGoogle Scholar
  10. 10.
    Shafrir Y, Prensky AL. Acquired epileptiform opercular syndrome: a second case report, review of the literature, and comparison to the Landau-Kleffner syndrome. Epilepsia. 1995;36:1050–7.PubMedGoogle Scholar
  11. 11.•
    Guerrini R, Pellacani S. Benign childhood focal epilepsies. Epilepsia. 2012;53 Suppl 4:9–18. Comprehensive review of the BECTS literature. PubMedGoogle Scholar
  12. 12.
    Northcott E, Connolly AM, Berroya A, et al. The neuropsychological and language profile of children with benign rolandic epilepsy. Epilepsia. 2005;46:924–30.PubMedGoogle Scholar
  13. 13.
    Hommet C, Billard C, Motte J, et al. Cognitive function in adolescents and young adults in complete remission from benign childhood epilepsy with centro-temporal spikes. Epileptic Disord. 2001;3:207–16.PubMedGoogle Scholar
  14. 14.
    Baglietto MG, Battaglia FM, Nobili L, et al. Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or rolandic spikes. Dev Med Child Neurol. 2001;43:407–12.PubMedGoogle Scholar
  15. 15.
    Croona C, Kihlgren M, Lundberg S, Eeg-Olofsson O, Eeg-Olofsson KE. Neuropsychological findings in children with benign childhood epilepsy with centrotemporal spikes. Dev Med Child Neurol. 1999;41:813–8.PubMedGoogle Scholar
  16. 16.
    Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological, intellectual, and behavioral findings in patients with centrotemporal spikes with and without seizures. Dev Med Child Neurol. 1997;39:646–51.PubMedGoogle Scholar
  17. 17.
    Massa R, de Saint Martin ARC. EEG criteria predictive of complicated evolution in idiopathic rolandic epilepsy. Neurology. 2001;57:1071–9.PubMedGoogle Scholar
  18. 18.
    Riva D, Vago C, Franceschetti S, et al. Intellectual and language findings and their relationship to EEG characteristics in benign childhood epilepsy with centrotemporal spikes. Epilepsy Behav. 2007;10:278–85.PubMedGoogle Scholar
  19. 19.
    Monjauze C, Tuller L, Hommet C, Barthez MA, Khomsi A. Language in benign childhood epilepsy with centro-temporal spikes abbreviated form: rolandic epilepsy and language. Brain Lang. 2005;92:300–8.PubMedGoogle Scholar
  20. 20.
    Staden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Language dysfunction in children with rolandic epilepsy. Neuropediatrics. 1998;29:242–8.PubMedGoogle Scholar
  21. 21.
    Clarke T, Strug LJ, Murphy PL, et al. High risk of reading disability and speech sound disorder in rolandic epilepsy families: case-control study. Epilepsia. 2007;48:2258–65.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Papavasiliou A, Mattheou D, Bazigou H, Kotsalis C, Paraskevoulakos E. Written language skills in children with benign childhood epilepsy with centrotemporal spikes. Epilepsy Behav. 2005;6:50–8.PubMedGoogle Scholar
  23. 23.
    Aicardi J, Chevrie JJ. Atypical benign partial epilepsy of childhood. Dev Med Child Neurol. 1982;24:281–92.PubMedGoogle Scholar
  24. 24.
    Doose H, Brigger-Heuer B, Neubauer B. Children with focal sharp waves: clinical and genetic aspects. Epilepsia. 1997;38:788–96.PubMedGoogle Scholar
  25. 25.
    Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic SF. Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation. Ann Neurol. 1995;38:633–42.PubMedGoogle Scholar
  26. 26.
    Roll P, Rudolf G, Pereira S, et al. SRPX2 mutations in disorders of language cortex and cognition. Hum Mol Genet. 2006;15:1195–207.PubMedGoogle Scholar
  27. 27.
    Kugler SL, Bali B, Lieberman P, et al. An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorder. Epilepsia. 2008;49:1086–90.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Michelucci R, Scudellaro E, Testoni S, et al. Familial epilepsy and developmental dysphasia: description of an Italian pedigree with autosomal dominant inheritance and screening of candidate loci. Epilepsy Res. 2008;80:9–17.PubMedGoogle Scholar
  29. 29.
    Robinson RO, Baird G, Robinson G, Simonoff E. Landau-Kleffner syndrome: course and correlates with outcome. Dev Med Child Neurol. 2001;43:243–7.PubMedGoogle Scholar
  30. 30.
    Lanzi G, Veggiotti P, Conte S, Partesana E, Resi C. A correlated fluctuation of language and EEG abnormalities in a case of the Landau-Kleffner syndrome. Brain Dev. 1994;16:329–34.PubMedGoogle Scholar
  31. 31.
    Cole AJ, Andermann F, Taylor L, et al. The Landau-Kleffner syndrome of acquired epileptic aphasia: unusual clinical outcome, surgical experience, and absence of encephalitis. Neurology. 1988;38:31–8.Google Scholar
  32. 32.
    Rossi PG, Parmeggiani A, Posar A, Scaduto MC, Chiodo S, Vatti G. Landau-Kleffner syndrome (LKS): long-term follow-up and links with electrical status epilepticus during sleep (ESES). Brain Dev. 1999;21:90–8.PubMedGoogle Scholar
  33. 33.
    Soprano AM, Garcia EF, Caraballo R, Fejerman N. Acquired epileptic aphasia: neuropsychologic follow-up of 12 patients. Pediatr Neurol. 1994;11:230–5.PubMedGoogle Scholar
  34. 34.
    Nevsimalova S, Tauberova A, Doutlik S, Kucera V, Dlouha O. A role of autoimmunity in the etiopathogenesis of Landau-Kleffner syndrome? Brain Dev. 1992;14:342–5.PubMedGoogle Scholar
  35. 35.
    Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999;134:607–13.PubMedGoogle Scholar
  36. 36.
    Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–399.Google Scholar
  37. 37.
    Vadlamudi L, Harvey AS, Connellan MM, et al. Is benign rolandic epilepsy genetically determined? Ann Neurol. 2004;56:129–32.PubMedGoogle Scholar
  38. 38.
    Vadlamudi L, Kjeldsen MJ, Corey LA, et al. Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration. Epilepsia. 2006;47:550–5.PubMedGoogle Scholar
  39. 39.
    Feekery CJ, Parry-Fielder B, Hopkins IJ. Landau-Kleffner syndrome: six patients including discordant monozygotic twins. Pediatr Neurol. 1993;9:49–53.PubMedGoogle Scholar
  40. 40.
    Vears DF, Tsai MH, Sadleir LG, et al. Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2012;53:319–24.PubMedGoogle Scholar
  41. 41.•
    Lesca G, Rudolf G, Labalme A, et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia. 2012;53:1526–38. This paper identifies copy number variants in LKS and ECSWS, many which highlight genomic regions or genes associated with ASD or speech and language disorders. PubMedGoogle Scholar
  42. 42.
    De Tiege X, Goldman S, Verheulpen D, Aeby A, Poznanski N, Van Bogaert P. Coexistence of idiopathic rolandic epilepsy and CSWS in two families. Epilepsia. 2006;47:1723–7.PubMedGoogle Scholar
  43. 43.••
    Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45:1061–6. One of the three seminal papers published together (Carvill et al. 2013; Lesca et al. 2013; Lemke et al. 2013) identifying GRIN2A as the first monogenic cause of EAS disorders. Until this discovery, the pathophysiological basis of these disorders was unknown and controversial. They showed that 20 % of unrelated probands with EAS had GRIN2A mutations. PubMedGoogle Scholar
  44. 44.••
    Lemke JR, Lal D, Reinthaler EM. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067–72. One of the three seminal papers published together (Carvill et al. 2013; Lesca et al. 2013; Lemke et al. 2013) identifying GRIN2A as the first monogenic cause of EAS disorders. Until this discovery, the pathophysiological basis of these disorders was unknown and controversial. PubMedGoogle Scholar
  45. 45.••
    Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45:1073–6. One of the three seminal papers published together (Carvill et al. 2013; Lesca et al. 2013; Lemke et al. 2013) identifying GRIN2A as the first monogenic cause of EAS disorders. Until this discovery, the pathophysiological basis of these disorders was unknown and controversial. This paper showed that 9 % of EAS probands had GRIN2A mutations. PubMedGoogle Scholar
  46. 46.
    Reutlinger C, Helbig I, Gawelczyk B, et al. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. Epilepsia. 2010;51:1870–3.PubMedGoogle Scholar
  47. 47.
    Conroy J, McGettigan PA, McCreary D, et al. Towards the identification of a genetic basis for Landau-Kleffner syndrome. Epilepsia. 2014;55:858–65.PubMedGoogle Scholar
  48. 48.
    Miyamoto H, Katagiri H, Hensch T. Experience-dependent slow-wave sleep development. Nat Neurosci. 2003;6:553–4.PubMedGoogle Scholar
  49. 49.
    Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995;269:1737–40.PubMedGoogle Scholar
  50. 50.
    Laube B, Hirai H, Sturgess M, Betz H, Kuhse J. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron. 1997;18:493–503.PubMedGoogle Scholar
  51. 51.
    Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science. 1992;256:1217–21.PubMedGoogle Scholar
  52. 52.
    Sprengel R, Suchanek B, Amico C, et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell. 1998;92:279–89.PubMedGoogle Scholar
  53. 53.
    Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021–6.PubMedGoogle Scholar
  54. 54.
    Akbarian S, Sucher NJ, Bradley D, et al. Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. J Neurosci. 1996;16:19–30.PubMedGoogle Scholar
  55. 55.
    Kosinski CM, Standaert DG, Counihan TJ, et al. Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: striatum and globus pallidus. J Comp Neurol. 1998;390:63–74.PubMedGoogle Scholar
  56. 56.
    Scherzer CR, Landwehrmeyer GB, Kerner JA, et al. Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: hippocampus and cortex. J Comp Neurol. 1998;390:75–90.PubMedGoogle Scholar
  57. 57.
    Conti F, Barbaresi P, Melone M, Ducati A. Neuronal and glial localization of NR1 and NR2A/B subunits of the NMDA receptor in the human cerebral cortex. Cereb Cortex. 1999;9:110–20.PubMedGoogle Scholar
  58. 58.
    Bi H, Sze CI. N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease. J Neurol Sci. 2002;200:11–8.PubMedGoogle Scholar
  59. 59.
    Hynd MR, Scott HL, Dodd PR. Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer’s disease. J Neurochem. 2004;90:913–9.PubMedGoogle Scholar
  60. 60.
    Clinton SM, Meador-Woodruff JH. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology. 2004;29:1353–62.PubMedGoogle Scholar
  61. 61.•
    Liegeois FJ, Morgan AT. Neural bases of childhood speech disorders: lateralization and plasticity for speech functions during development. Neurosci Biobehav Rev. 2012;36:439–58. Systematic review examining the evidence linking motor speech disorders (apraxia of speech and dysarthria) and brain abnormalities in children and adolescents with developmental, progressive or childhood-acquired conditions. PubMedGoogle Scholar
  62. 62.
    Belton E, Salmond CH, Watkins KE, Vargha-Khadem F, Gadian DG. Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Hum Brain Mapp. 2003;18:194–200.PubMedGoogle Scholar
  63. 63.
    Liegeois F, Baldeweg T, Connelly A, Gadian DG, Mishkin M, Vargha-Khadem F. Language fMRI abnormalities associated with FOXP2 gene mutation. Nat Neurosci. 2003;6:1230–7.PubMedGoogle Scholar
  64. 64.••
    Turner SJ, Mayes AK, Verhoeven A, Mandelstam SA, Morgan AT, Scheffer IE. GRIN2A: an aptly named gene for speech dysfunction. Neurology. 2015;84:586–93. Study delineating the distinctive speech phenotype associated with GRIN2A mutations, a finding that will readily aid in diagnosis. PubMedGoogle Scholar
  65. 65.
    Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001;413:519–23.PubMedGoogle Scholar
  66. 66.
    Spiteri E, Konopka G, Coppola G, et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am J Hum Genet. 2007;81:1144–57.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Vernes SC, Spiteri E, Nicod J, et al. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Am J Hum Genet. 2007;81:1232–50.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Morgan AT, Liegeois F, Vargha-Khadem F. Motor speech outcome as a function of the site of brain pathology: a developmental perspective. In: Maassen B, van Lieshout P, editors. Speech motor control: new developments in basic and applied research. Oxford: Oxford University Press; 2010. p. 95–115.Google Scholar
  69. 69.
    Turner SJ, Hildebrand MS, Block S, et al. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria. Am J Med Genet A. 2013;161A:2321–6.PubMedGoogle Scholar
  70. 70.
    Hurst JA, Baraitser M, Auger E, Graham F, Norell S. An extended family with a dominantly inherited speech disorder. Dev Med Child Neurol. 1990;32:352–5.PubMedGoogle Scholar
  71. 71.
    Feuk L, Kalervo A, Lipsanen-Nyman M, et al. Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet. 2006;79:965–72.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Zeesman S, Nowaczyk MJ, Teshima I, et al. Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A. 2006;140:509–14.PubMedGoogle Scholar
  73. 73.
    Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA. Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res. 2006;49:500–25.PubMedGoogle Scholar
  74. 74.
    Rice GM, Raca G, Jakielski KJ, et al. Phenotype of FOXP2 haploinsufficiency in a mother and son. Am J Med Genet A. 2012;158A:174–81.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Watkins KE, Dronkers NF, Vargha-Khadem F. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain. 2002;125:452–64.PubMedGoogle Scholar
  76. 76.
    Vargha-Khadem F, Watkins KE, Price CJ, et al. Neural basis of an inherited speech and language disorder. Proc Natl Acad Sci U S A. 1998;95:12695–700.PubMedCentralPubMedGoogle Scholar
  77. 77.•
    Lal D, Reinthaler EM, Altmuller J, et al. RBFOX1 and RBFOX3 mutations in rolandic epilepsy. PLoS One. 2013;8:e73323. Identifies deletions and truncating mutations of RBFOX1 and RBFOX3 in some individuals with rolandic epilepsy in complex pedigrees. PubMedCentralPubMedGoogle Scholar
  78. 78.
    Lal D, Trucks H, Moller RS, et al. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia. 2013;54:265–71.PubMedGoogle Scholar
  79. 79.
    Zhao WW. Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations. Mol Cytogenet. 2013;6:26.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Elia J, Glessner JT, Wang K, et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet. 2012;44:78–84.PubMedCentralGoogle Scholar
  81. 81.
    Davis LK, Maltman N, Mosconi MW, et al. Rare inherited A2BP1 deletion in a proband with autism and developmental hemiparesis. Am J Med Genet A. 2012;158A:1654–61.PubMedGoogle Scholar
  82. 82.
    Martin CL, Duvall JA, Ilkin Y, et al. Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:869–76.PubMedGoogle Scholar
  83. 83.
    Bhalla K, Phillips HA, Crawford J, et al. The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. J Hum Genet. 2004;49:308–11.PubMedGoogle Scholar
  84. 84.
    Fogel BL, Wexler E, Wahnich A, et al. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet. 2012;21:4171–86.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Gehman LT, Stoilov P, Maguire J, et al. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat Genet. 2011;43:706–11.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Dredge BK, Jensen KB. NeuN/Rbfox3 nuclear and cytoplasmic isoforms differentially regulate alternative splicing and nonsense-mediated decay of Rbfox2. PLoS One. 2011;6:e21585.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Ayub Q, Yngvadottir B, Chen Y, et al. FOXP2 targets show evidence of positive selection in European populations. Am J Hum Genet. 2013;92:696–706.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science. 2004;305:525–8.PubMedGoogle Scholar
  89. 89.
    Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6:e1000962.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974–85.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Kevelam SH, Jansen FE, Binsbergen E, et al. Copy number variations in patients with electrical status epilepticus in sleep. J Child Neurol. 2012;27:178–82.PubMedGoogle Scholar
  92. 92.•
    Dimassi S, Labalme A, Lesca G, et al. A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2. Epilepsia. 2014;55:370–8. This paper identifies 30 rare microduplication and microdeletions in patients with rolandic epilepsy. PubMedGoogle Scholar
  93. 93.•
    Reinthaler EM, Lal D, Lebon S, et al. 16p11.2 600 kb duplications confer risk for typical and atypical rolandic epilepsy. Hum Mol Genet. 2014;23:6069–80. This recent study demonstrates that duplications of 16p11.2 represent a significant genetic risk factor for typical and atypical rolandic epilepsy. PubMedGoogle Scholar
  94. 94.
    Rodenas-Cuadrado P, Ho J, Vernes SC. Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet. 2014;22:171–8.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Strauss KA, Puffenberger EG, Huentelman MJ, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354:1370–7.PubMedGoogle Scholar
  96. 96.
    Consortium SLI. Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet. 2004;74:1225–38.Google Scholar
  97. 97.
    Kwasnicka-Crawford DA, Carson AR, Roberts W, et al. Characterization of a novel cation transporter ATPase gene (ATP13A4) interrupted by 3q25-q29 inversion in an individual with language delay. Genomics. 2005;86:182–94.PubMedGoogle Scholar
  98. 98.
    Sharp AJ, Mefford HC, Li K, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008;40:322–8.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Ballif BC, Hornor SA, Jenkins E, et al. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet. 2007;39:1071–3.PubMedGoogle Scholar
  100. 100.
    Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148:1223–41.PubMedCentralPubMedGoogle Scholar
  101. 101.
    Laffin JJ, Raca G, Jackson CA, Strand EA, Jakielski KJ, Shriberg LD. Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization. Genet Med. 2012;14:928–36.PubMedCentralPubMedGoogle Scholar
  102. 102.
    Raca G, Baas BS, Kirmani S, et al. Childhood apraxia of speech (CAS) in two patients with 16p11.2 microdeletion syndrome. Eur J Hum Genet. 2013;21:455–9.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Newbury DF, Mari F, Sadighi Akha E, et al. Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder. Eur J Hum Genet. 2013;21:361–5.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Neubauer BA, Fiedler B, Himmelein B, et al. Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14. Neurology. 1998;51:1608–12.PubMedGoogle Scholar
  105. 105.
    Hoppman-Chaney N, Wain K, Seger PR, Superneau DW, Hodge JC. Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype. Clin Genet. 2013;83:345–51.PubMedGoogle Scholar
  106. 106.
    Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190–8.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Dodd B. Differential diagnosis and treatment of children with speech disorder. 2nd ed. London: Whurr; 2005.Google Scholar
  108. 108.
    Broomfield J, Dodd B. Children with speech and language disability: caseload characteristics. Int J Lang Commun Disord. 2004;39:303–24.PubMedGoogle Scholar
  109. 109.
    ASHA. Childhood apraxia of speech [technical report].
  110. 110.
    Darley FL, Aronson AE, Brown JR. Clusters of deviant speech dimensions in the dysarthrias. J Speech Hear Res. 1969;12:462–96.PubMedGoogle Scholar
  111. 111.
    Darley FL, Aronson AE, Brown JR. Differential diagnostic patterns of dysarthria. J Speech Hear Res. 1969;12:246–69.PubMedGoogle Scholar
  112. 112.
    Onslow M. Behavioural management of stuttering. 1st ed. Sydney: Livingston; 1993.Google Scholar
  113. 113.
    ASHA. Definitions of communication disorders and variations [relevant paper]. 1993.Google Scholar
  114. 114.
    Bishop DV. Ten questions about terminology for children with unexplained language problems. Int J Lang Commun Disord. 2014;49:381–415.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Reilly S, Tomblin B, Law J, et al. Specific language impairment: a convenient label for whom? Int J Lang Commun Disord. 2014;49:416–51.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Samantha J. Turner
    • 1
    • 2
    • 6
  • Angela T. Morgan
    • 1
    • 2
    • 3
  • Eliane Roulet Perez
    • 4
  • Ingrid E. Scheffer
    • 1
    • 5
    • 6
  1. 1.Department of Paediatrics, The University of MelbourneThe Royal Children’s HospitalParkvilleAustralia
  2. 2.Language and Literacy GroupMurdoch Childrens Research InstituteParkvilleAustralia
  3. 3.Speech Pathology DepartmentThe Royal Children’s HospitalParkvilleAustralia
  4. 4.Paediatric Neurology and Neurorehabilitation UnitHospitalier Universitaire VaudoisLausanneSwitzerland
  5. 5.Florey Institute of Neuroscience and Mental HealthMelbourneAustralia
  6. 6.Epilepsy Research Centre, Department of MedicineUniversity of Melbourne, Austin HealthMelbourneAustralia

Personalised recommendations