Genetics of Speech Sound Disorders: Research and Clinical Implications

Transcription

1 Genetics of Speech Sound Disorders: Research and Clinical Implications Barbara Lewis, PHD, CCC-SLP Case Western Reserve University

2 Conflict of Interest Disclosure I have no financial or non financial interest or related personal interest of bias in any organization whose products or services are described, reviewed, evaluated or compared in this presentation.

3 Outline for Today s Talk A. The study of genes: Speech and language disorders as a complex trait B. Common and rare variants for Speech Sound Disorders C.Adolescent and adult outcomes for individuals with early histories of SSD: What predicts outcome? D.Future directions: Genetic Imaging and Epigenetics? E. Questions?

4 THE STUDY OF GENES: SPEECH AND LANGUAGE DISORDERS AS A COMPLEX TRAIT

5 Goals of Genetic Research 1. Identify genes 2. Expression in Brain 3. Behavior

6 Pedigree of SSD Alone Proband Dyslexia R LD Late talker Lang R Speech Late talker Late talker Language 2013, Barbara A. Lewis, All rights Reserved

7 Pedigree of SSD + Language Impairment+ Reading Disorder Proband R Sp Matric Phon Artic Artic Read Sp LD Artic Read Sp Artic R Sp Artic R Sp LD Artic Artic Stut Lang ADD R, Sp Late talker 2013, Barbara A. Lewis, All rights Reserved

8 Speech and Language Disorders are a Multifactorial Complex Trait ENVIRONMENT/ DEMOGRAPHIC Ethnicity/Social Age Socioeconomic Oral-motor Development GENETIC Genotype PHENOTYPE Speech-sound only (Narrow) Speech-sound and Language (Broad) Speech-sound, Language, or Reading (V. Broad) CLINICAL Remediation

9 Genetic Architecture of a Complex Trait SSD, LI, or RD Environmental factors Endophenotypes

10 Definition of Endophenotypes Objectively measurable biophysiologic, neuroanatomical, cognitive, or neuropsychological parameters that are closely associated with a behavioral trait and useful on detecting genetic influences. A psychiatric concept and a special kind of biomarker. The purpose of the concept is to divide behavioral symptoms into more stable phenotypes with a clear genetic connection. Endophenotypes are presumed to be simpler than a clinical phenotype and more directly related to genes. Gottesman, I.I. & Gould, T.D. (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry, 160,

11 Multiple Deficit Model (Pennington, 2006; McGrath et al, 2007) Multi-factorial etiology Constellation of risk and protective factors determine outcomes Co-morbidity of disorders (SSD, RD, LI, ADHD) occurs when risk factors are shared. Shared risk factors may in part be genetic Generalist genes have broad influences on neural processes and may account for shared risk factors Some candidate genes influence neural development and may impact multiple cognitive skills. Other genes may make a unique contribution to a single disorder.

12 Some genetic considerations when studying a complex human trait No single gene is responsible for the majority of cases or deficit of any particular developmental disorder. Multiple heterogeneous effects of risk genes may act alone or together to give rise to multiple profiles of skills culminating in the same diagnosis and general impairment on the surface. A single genetic defect may result in multiple problems if it is present early in development.

13 Some genetic considerations when studying a complex human trait (continued) Different components of this complex phenotype could be linked to distinct genetic loci. Nature and severity of the disorder might vary at different developmental stages; genes may be turned on and off during the life span. Environmental effects may be unique to individuals (nonshared environment). Identifying broad encompassing environmental effects will be difficult.

14 What are specific genes that may underlie speech sound disorders? FOXP2: Located on 7q13; a brain expressed transcription factor that affects brain development; identified in the KE family (Liegeios et al., 2003). ROBO1 and ROBO2: Located on chromosome 3; guides axons and influences neuronal axon growth; identified in dyslexics in Finland (Nopola-Hemmi et al., 2001). KIAA0319, TTRAP, and DCDC2: Located on chromosome 6; genes disrupt neuronal migration; identified in dyslexic by numerous research groups (Grigorenko et al., 2000; Smith et al., 2007). BDNF: Brain-derived neurotrophic factor related to nerve growth and differentiation in the brain (Stein, unpublished). DYX8: Region on chromosome 1 that demonstrates pleiotropy for SSD and dyslexia (Miscamarra et. al., 2007). Aromatase (CYP19A1): Located on 15q21.2 ; This gene regulates estrogen synthesis in specific brain areas. It is related to synaptic plasticity and axonal growth (Anthoni et al., 2012).

15 COMMON AND RARE VARIANTS FOR SSD

16 Common and Rare Variants for SSD It is likely that both common and rare genetic variants contribute to SSD While the FOXP2 research has provided a model for the understanding of rare variants, there is a need for discovery and research of other such genes. Understanding shared functional neural pathways and genetic links across different disorders is critical. For example deficits in modulating neural plasticity may span several developmental disorders. Ultimately, discoveries must impact clinical practice by providing early diagnosis and targeted interventions.

17 Case Study of a Rare Genetic Mutation We identified three different communication disorders, Williams Syndrome, Autism, and Apraxia of Speech, in three siblings in a single family Our goal was to understand the genetic architecture in this family We used high-dimensional genetic data from a data chip with 2.5 million markers and exome sequencing to determine the common and uncommon genetic features of this family and examined this information with respect to the known phenotypic data

18 Family History

19 Why are we interested in studying the genetics of this family? WBS is caused by a deletion (loss) of ~1Mb on chromosome 7q11.22 encompassing genes Prevalence: 1/7,500 to 1/20,000 Typical features include mental retardation, visual spatial impairment, overfriendliness and strength in verbal skills Most importantly: numerous reports of dosage changes (partial deletions, duplications (Dup7), inversions etc.) on 7q11.22 are associated with other behavioral disorders including autism and speech/language (mostly expressive language) delays Conclusion: Dosage of genes in this region is important Hypothesis: Childhood apraxia of speech (CAS), Williams Syndrome and Autism share genetic determinants

20 Genes in the Williams deletion region show molecular functions that may be key to understanding CAS

21 Summary of genetic changes in family

22 RESULTS The child diagnosed with Williams Syndrome had a predicted hemizygous deletion (Copy Number = 1) overlapping the Williams deletion region. This deletion was predicted to be 1.4 Mb based on boundary probe position (chr7: ) and covered 25 genes

23 Comparison of FISH between Williams Sib (left) and Apraxic Child (right)

24 The sibling with Autism shows a different arrangement of chromosomes in this region The child diagnosed with autism had a run of homozygosity that partially overlapped the Williams region. The run of homozygosity was predicted to be 1.1 Mb based on boundary probe position (chr7: ) and covered 18 genes The region of chromosome 7 in the mother and the father are virtually identical (potentially because of assortative mating)

25 Genetic Findings Child with Williams: Typical haploinsufficient in the 7q11.22 region. Wild-type gene provides insufficient product to fulfill normal cell function Child with autism: The copy of one of the two chromosomes from the mother and the father is virtually identical in this region Child with Apraxia of Speech (proband) shows no altered structural arrangements in this region. Our exome sequencing showed that she had no obvious mutations in FOXP2, CNTNAP2, ROBO1, DCDC2, KIAA0319

26 Conclusions and Future Directions We found a clear genetic link between two sibs with Williams-Beuren Syndrome and Autism on chromosome 7q11.22, but not with Apraxia of Speech Ongoing work on the exome of this family We are performing similar detailed experiments in other families with childhood apraxia of speech and other speech sound disorders Our data show that speech sound disorders have heterogeneous origin: variation in copy number, variation in coding exonic changes, variation in noncoding regions play a role

27 Common Genetic Variants: Neural pathway genes Dopamine D2 receptor (DRD2): associated with disfluent speech, stuttering in children with Tourette s syndrome, and verbal skills as measured by the PPVT. The dopaminergic system is involved in motor control, endocrine function, cognition, and language learning, procedural learning, and working memory. AVP receptor 1a (AVPR1a): associated with language impairment in autistic children. Arginine-vasopressin (AVP) is involved in social behavior and vocalization. ASPM: causes microcephaly, is involved in mitotic spindle formation, neurogenesis, cognition, and is associated with intracranial volume. It has been associated with single word reading and speech sound production proficiency Examination of positive selective pressure on ASPM and its coevolution with language have lead to the hypothesis that ASPM may be related to language development.

28 Methods Participants N=556 individuals from 199 families. 50.6% were diagnosed with SSD. Endophenotypes Phonological Memory: Nonsense Word Repetition and Multisyllabic Real Word Repetition Reading Decoding: Word Identification and Word Attack subtests of the Woodcock Reading Mastery Tests. Vocabulary: Peabody Picture Vocabulary Test and Expressive One Word Picture Vocabulary Test Genotyping 4 SNPs in ASPM, 7 SNPs in AVPR1a, and 27 SNPs in DRD2 Analysis Association analyses were conducted using a method that models familial correlation as a polygenic random effect and genotypes as fixed effects.

29 Results DRD2, AVPR1a, and ASPM are all associated with measures of receptive vocabulary, phonological memory, and reading decoding. We hypothesized that DRD2 s role in cognition, learning, visuospatial skills, and especially working memory are also important for phonological memory. Our observed association with PPVT replicates a previously reported association with Picture Vocabulary, and reflects dopamine s role in language learning. AVPR1a has previously been associated with decreased language ability in autistic children. Our results suggest that AVRPR1a has a role in language development. These findings replicate a report of association between a SNP in ASPM and single word reading and speech sound production proficiency.

30 ADOLESCENT AND ADULT OUTCOMES FOR INDIVIDUALS WITH EARLY HISTORIES OF SSD OF SUSPECTED GENETIC ORIGIN

31 Linkage Results for Spoken Language and Written Expression (Lewis et al., 2011) Chromosome Spoken Language at Early Childhood Written Expression at School-age Chromosome 1 Articulation Written vocabulary Vocabulary Reading decoding Phon. Memory Spelling Chromosome 3 Articulation Written vocabulary Vocabulary Spelling Phon, Memory Reading decoding Speeded Naming Chromosome 6 Vocabulary Spelling Phon. Memory Chromosome 15 Oral Motor Reading decoding Articulation Spelling Phonological Memory

32 Participants N=345 Identified at early childhood (4-6 years) through a proband child with a moderate to severe SSD. At early childhood participants were grouped as: SSD only n=84 SSD + LI n=102 No SSD n=159 (siblings) Participants were followed longitudinally assessed at: Early childhood (4-6 yrs) School age (8-10 yrs) Adolescence (11-18 yrs) Adulthood (18+ years) At adolescence participants were groups as: Resolved SSD n=119 Low performance on multisyllabic word repetition n=33 Residual errors in conversational speech in addition to low MSW n=43 No SSD n=150 (siblings)

33 Measures at Adolescence Speech sound measures Multisyllabic word repetition Non-word repetition Conversational speech sample Fletcher Time-by-Count Spoken Language Peabody Picture Vocabulary Test -4 th Ed. Expressive One Word Picture Vocabulary Test- 2 nd Ed. Clinical Evaluation of Language Fundamentals -4 Screening Test Written Language Word ID and Word Attack of Woodcock Reading Mastery Tests-Revised Reading Comprehension of Wechsler Individual Achievement Test Test of Written Spelling 4 th Ed. Cognitive Abilities Wechsler Adult Intelligence Scale Revised (PIQ)

34 Comparisons of SSD groups to No SSD group Resolved SSD vs. No SSD: poorer on Non-word Repetition, CELF-4, Word Attack, and Reading Comprehension. Low MSW group vs No SSD: poorer on all measures except the Fletcher Time by Count PSD vs No SSD: poorer on all measures

35 Comparisons of SSD Groups Low MSW vs Resolved SSD: poorer on all measures except Fletcher Time-by- Count PSD vs Resolved SSD: poorer on all measures PSD vs. Low MSW: poor on non-word repetition and Fletcher Time-by-Count

36 Conclusions Early childhood SSD impacts long term speech, language, and literacy outcomes even when the overt SSD resolves. Individuals with histories of SSD may have difficulty on repetition of multisyllabic words even when they do not have errors in conversational speech. This may indicate weak phonological representations or phonological processing skills. Individuals whose speech errors persist in conversation at adolescence are at greatest risk for poor speech, language and literacy outcomes. These individuals may have both weak phonological representations as well as residual articulatory difficulties. Adolescent outcomes may be influenced by genetic factors as well as intervention history.

37 FUTURE DIRECTIONS: GENETIC IMAGING AND EPIGENTICS

38 The Emerging Field of Imaging Genetics Imaging genetics is the use of imaging technology as a phenotype to evaluate how genes that influence disorders are expressed in the brain. Both genetics and environment are important in determining brain function. Integrating genetics with neuroimaging will improve our understanding of speech and language disorders. There is a need for novel analytic, statistical and visualization techniques.

39 On the left, controls without a history of speech and language disorders show the expected activation in the language areas while repeating nonsense words. On the right, paticipants with a history of speech sound disorders show under activation of the language areas during repetition of nonsense words.

40 Whole Exome Sequencing: sequence protein coding regions of the genome rather than full genome; 180,000 exons make up 1% of the genome but code for 85% of disease mutations.

41 The evolution of a giraffe s neck is often used as the example in explanations of Lamarckism.The identification of Lamarckism with the inheritance of acquired characteristics is regarded by some as an artifact of the subsequent history of evolutionary thought, repeated in textbooks without analysis.

42 Epigenetics The study of inherited changes in the phenotype by mechanisms other than DNA Non-genetic factors cause genes to behave differently. Can be transmitted through multiple generations. Terms such as epigenome, epigenetic code, epigenetic map parallel genetic terms. Epigentic changes occur through processes such as methylation. Developmental disorders may be transmitted through epigenetics. Emphasizes that early life experiences can create lasting changes in behavior for example formation and maintenance of memories.

43 Conclusions and Future Directions Both rare and common variants contribute to SSD. In some families, a single rare variant may result in SSD, while in others, various combinations of risk genes may result in a of SSD. Different combinations of genes may give rise to different phenotypes within a single family. Carefully selected endophenotypes for genetic studies are essential as they may help us identify genes unique to speech sound disorders. Studies of long-term outcomes for individuals with SSD may help us identify predictive factors that differentiate those individuals with recovered versus persistent disorders.

44 Clinical Implications An improved understanding of the genetic and neurological underpinnings of speech sound disorders will: Identify the biological mechanisms that underlie both typical and disordered speech. Aid in the early identification of children at risk for speech sound disorders. Facilitate the development of more specific and effective therapies. Early identification and more effective therapies will result in improved long-term academic, occupational and social outcomes.

45 . References Anthoni, H., Sucheston, L.E., Lewis, B.A., Tapia-Paez, I., Fan, X., Zucchelli, M., Taipale, M., Stein, C.M. et al. (2012). The Aromatase Gene CYP19A1: Several genetic and functional lines of evidence supporting a role in reading, speech and language. Behavior Genetics, 42(4), Gottesman, I.I. & Gould, T.D. (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry, 160, Pennington, B.F. (2006). From single to multiple deficit models of developmental disorders. Cognition, 101, Hurst, J.A., Baraitser, M., Auger, E., Graham, F., & Norell, S. (1990). An extended family with a dominantly inherited speech disorder. Developmental Medicine and Child Neurology, 32, Jablonka, E., & Lamb, M.J. (2002). The changing concept of epigenetics. Ann. N.Y. Acad. Sci., 981, Lai, CS, Fisher, SE, Hurst, JA et al. A fork-head domain gene is mutated in a severe speech and language disorder. Nature, 413, Liegeois, F., Baldeweg, T., Connelly, A., Gadian, D. G., Mishkin, M., & Vargha-Khadem, F. (2003). Language fmri abnormalities associated with FOXP2 gene mutation. Nat Neurosci, 6(11), Lennon, P.A., Cooper, M.L., Peiffer, D.A., Gunderson, K.L., Patel, A., Peters, S. et al. (2007). Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: Clinical report and review. American Journal of Medical Genetics,143, Lewis, B.A. (2008). Genetics of speech sound disorders and neurological correlates. Paper presented at the American Speech, Language and Hearing Association Annual Convention, Chicago, IL. Lewis, B.A., Freebairn, L., Heeger, S., & Cassidy, S.B. (2002). Speech and language skills of individuals with Prader Willi Syndrome. American Journal of Speech Language Pathology, 11, Lewis, B. A., Shriberg, L.D., Freebairn, L.A., Hansen, A.J., Stein, C.M., Taylor, H.G.& Iyengar, S.K. (2006). The genetic bases of speech sound disorders: evidence from spoken and written language. J. Speech Lang Hear. Res. 49,

46 References Continued Lewis, B., Avrich, A., Freebairn, L., Hansen, A., Sucheston, L., Kuo, I., Taylor, H.G., Iyengar, S., Stein, C. Outcomes of children with speech sound disorders: Impact of endophenotypes. Journal of Speech Language and Hearing Research, 54, MacDermot, K.D., Bonora, E., Sykes, N., et al. (2005). Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. American Journal of Human Genetics, 76, McGrath, L.M., Pennington, B.F., Willcutt, E.G., Boada, R., Shriberg, L.D., & Smith, S.D. (2007). Gene X Environment interactions in speech sound disorders predict language and preliteracy outcomes. Development and Psychopathology, 19, Miscamarra, L., Stein, C.M., Millard, C., Kluge, A., Cartier, K.C., Freebairn, L.A. et al. (2007). Further evidence of pleiotropy influencing speech and language: Analysis of the DYX8 region. Human Heridity, 63, Pennington, B.F. (2006). From single to multiple deficit models of developmental disorders. Cognition, 101, Shriberg, L.D., Ballard, K.J., Tomblin, J.B., Duffy, J.R., Odell, K.H., & Williams, C.A. (2006). Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. Journal of Speech, Language, and Hearing Research, 49, Shriberg, L.D., Potter, N.L., & Strand, E.A.,(in press). Prevalence and phenotype of childhood apraxia of speech in youth with galactosemia. Journal of Speech, Language, and Hearing Research. Skebo, C.M., Lewis, B.A., Freebairn, L.A., Tag, J., Ciesla,A.A., & Stein, C.M. (2013). Reading skills of students with speech sound disorders at three stages of literacy development. Language Speech and Hearing Services in the Schools, 44, Smith, S.D. (2011). Approach to epigenetic analysis in language disorders. J. of Neurodevelopmental Disorders, Stein, C. M., Schick, J.H., Taylor, G.H., Shriberg, L.D., Millard, C., Kundtz-Kluge, A. et al. (2004). Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading. Am. J. Hum. Genet. 74, Stein, C. M., Miller, C., Kluge, A., Miscimarra, L.E., Cartier, K.C., Freebairn, L.A. et al. (2006). Speech Sound Disorder Influenced by a Locus in 15q14 Region. Behav. Genetics, 36(6), Tkach, J.A., Chen, X., Freebairn, L.A., Schmithorst, V.J., Holland, S.K., & Lewis, B.A. (i2011). Neural Correlates of Phonological Processing in Speech Sound Disorder: A Functional Magnetic Resonance Imaging Study, Brain and Language. 119, Wilcke, A., Ligges, C., Burkhardt, J., Alexander, M., Wolf C., Quente, E. et al. (2012). Imaging genetics of FOXP2 in dyslexia. European Journal of Human Genetics, 20, Worthey, E.A., Raca, G., Laffin, J.J., Wilk, B.M., Harris, J.M., Jakielski, K., Dimmock, D.P., Strand, E.A., & Shriberg, L.D. (2013). Whole exome sequencing supports genetic heterogeneity in childhood apraxia of speech. Journal of Neurodevelopmental Disorders,

47 Collaborating Laboratories Case Western Reserve University (Epidemiology and Biostatistics) Sudha Iyengar, PhD Catherine Stein, PhD Alison Avrich Ciesla M.S. Robert Elston, PhD Barbara Truitt, MS University of Wisconsin Madison Lawrence D. Shriberg, PhD University of Cincinnati Erin Redle, PhD Jean Tkach, PhD Scott Holland, PhD Jennifer Vannest, PhD Case Western Reserve University (Psychological Sciences) Barbara Lewis, PhD Elizabeth Short, PhD Lee Thompson, PhD Lisa Freebairn, M.A. Jessica Tag, M.A. Case Western Reserve University (Pediatrics) Gerry Taylor, PhD SUNY Buffalo Lara Miscamarra, PhD

48 Grants Acknowledgement This research was supported by grants from the National Institutes of Health, National Institute on Deafness and other Communication Disorders: R01DC [Lewis] R01DC [Iyengar]

49 QUESTIONS?