Genetic Variations and Associated Electrophysiological and Behavioral Traits
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ASU Digital Repository Genetic Variations and Associated Electrophysiological and Behavioral Traits in Children with Childhood Apraxia of Speech by Caitlin Vose A Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Approved April 2018 by the Graduate Supervisory Committee: Beate Peter, Chair Li Liu Gene Brewer ARIZONA STATE UNIVERSITY May 2018 ABSTRACT Childhood Apraxia of Speech (CAS) is a severe motor speech disorder that is difficult to diagnose as there is currently no gold-standard measurement to differentiate between CAS and other speech disorders. In the present study, we investigate underlying biomarkers associated with CAS in addition to enhanced phenotyping through behavioral testing. Cortical electrophysiological measures were utilized to investigate differences in neural activation in response to native and non-native vowel contrasts between children with CAS and typically developing peers. Genetic analysis included full exome sequencing of a child with CAS and his unaffected parents in order to uncover underlying genetic variation that may be causal to the child’s severely impaired speech and language. Enhanced phenotyping was completed through extensive behavioral testing, including speech, language, reading, spelling, phonological awareness, gross/fine motor, and oral and hand motor tasks. Results from cortical electrophysiological measures are consistent with previous evidence of a heightened neural response to non-native sounds in CAS, potentially indicating over specified phonological representations in this population. Results of exome sequencing suggest multiple genetic variations contributing to the severely affected phenotype in the child and provide further evidence of heterogeneous genomic pathways associated with CAS. Finally, results of behavioral testing demonstrate significant impairments evident across tasks in CAS, suggesting underlying sequential processing deficits in multiple domains. Overall, these results have the potential to delineate functional pathways from genetic variations to the brain to observable behavioral phenotypes and motivate the development of preventative and targeted treatment approaches. i TABLE OF CONTENTS Page LIST OF TABLES .......................................................................................................... iv LIST OF FIGURES ......................................................................................................... v CHAPTER 1 INTRODUCTION ................................................................................................1 Childhood Apraxia of Speech: Behavioral Traits and Burden ................1 Sequential Processing and CAS .......................................................... 10 Brain Correlates of CAS .................................................................... 13 Genetic Influences on CAS ................................................................ 17 Gene-Brain-Behavior Connection ...................................................... 20 Research Questions ............................................................................ 22 General Methods: Participants ............................................................ 24 2 EXPERIMENT 1: BEHAVIORAL ASPECTS OF CHILDHOOD APRAXIA OF SPEECH AND THE SEQUENTIAL PROCESSING DEFICIT ........ 27 Method .............................................................................................. 27 Results .............................................................................................. 37 Discussion ......................................................................................... 43 3 EXPERIMENT 2: PERCEPTION OR PRODUCTION? AN EEG STUDY OF VOWELS IN CAS ........................................................................... 54 Methods ............................................................................................ 54 Results .............................................................................................. 58 Discussion ......................................................................................... 63 ii CHAPTER Page 4 EXPERIMENT 3: GENETIC VARIATION IN A TRIO WITH CAS ................. 70 Method .............................................................................................. 70 Results .............................................................................................. 77 Discussion ......................................................................................... 84 5 INTEGRATED DISCUSSION ........................................................................... 90 REFERENCES…...……………………………………………………………………94 APPENDIX A PARENT QUESTIONNAIRE………………………………………………….104 B INDIVIDUAL SCORES FOR DEMOGRAPHIC DATA……………………...112 C OPERATIONAL DEFINITIONS FOR CAS CHARACTERISTICS………….113 D SPEECH AND LANGUAGE GENES OF INTEREST………………………..115 iii LIST OF TABLES Table Page 1. Participant Characteristics ....................................................................................... 25 2. Core and Co-Occurring Characateristics of CAS ..................................................... 38 3. T tests Comparing Confirmatory Measures .............................................................. 40 4. T tests Comparing Experimental Measures .............................................................. 41 5. Summary of Motor Results and t tests Comparing CAS and TD .............................. 42 6. Correlations and Significance Level for Experimental Tasks ................................... 43 7. Mean and Standard Deviation of Recorded Average Amplitudes ............................. 59 8. Mean and Standard Deviation of Difference Calculations and t tests ........................ 60 9. De Novo Variants .................................................................................................... 79 10. X-Linked Recessive Variants................................................................................... 80 iv LIST OF FIGURES Figure Page 1. Gene-Brain-Behavior Connection .......................................................................... 22 2. MMN Electrode Montage ...................................................................................... 57 3. Grand-Averaged Responses to N/NN Vowels at Frontal Electrode Sites for CAS .. 60 4. Grand-Averaged Responses to N/NN Vowels at Frontal Electrode Sites for TD .... 61 5. Difference Waves for N/NN Vowels at Frontal Electrode Sites for CAS and TD ... 61 6. Grand-Averaged Responses to CP Vowels at Frontal Electrode Sites for CAS ....... 62 7. Grand-Averaged Responses to CP Vowels at Frontal Electrode Sites for TD ......... 63 8. Difference Waves for CP Vowels at Frontal Electrode Sites for CAS and TD………………………………………..………………………………………….63 9. CoNIFER Results, Chromosome 14 (1). ................................................................ 78 10. CoNIFER Results, Chromosome 14 (2). ................................................................ 78 v CHAPTER 1 INTRODUCTION Childhood Apraxia of Speech: Behavioral Traits and Burden Childhood apraxia of Speech (CAS) is a severe motor speech disorder that has a substantial impact on a child’s ability to communicate functionally across environments. The American Speech and Hearing Association (ASHA) describes CAS as having three main characteristics, including inconsistent speech errors on repeated productions, lengthened and disrupted co-articulatory transitions and inappropriate prosody (ASHA 2007). Additional characteristics of CAS include vowel distortions, lack of differentiation between stressed and unstressed syllables, mis-stressing syllables, and difficulty with multisyllabic words (Shriberg et al., 2011). For purposes of this study, it is important to note that vowel distortions, in particular, are highly unusual in typical speech and delayed speech development at any age. Although these characteristics of CAS have been well established, it has also been suggested that CAS is a multi-level disorder involving auditory/perceptual deficits in addition to deficits in planning/programming of speech (Shriberg, Lohmeier, Strand, and Jakielski, 2012). CAS is remarkably complex, difficult to treat clinically, and places a heavy burden on children and families who are impacted. A better understanding of the biological causes and associations, in terms of genes, brain functions, and behavior, can lead to the earliest possible identification and development of novel and proactive interventions. Little is known about the etiology of this severe speech disorder, but it has been suggested to be a neurological sensorimotor speech sound disorder (SSD) subtype with a disruption of neurophysiological processes at the level of motor planning and/or 1 programming of speech movement sequences (ASHA, 2007). CAS may occur secondary to a known neurological injury such as intrauterine stroke or infection (Brown et al., 2000), neurodevelopmental disorder, or genetic mutation (Shriberg, Potter, & Strand, 2011), although in most cases, the cause is unknown (Murray, McCabe, Heard, & Ballard, 2015). It is well established that children with CAS require extensive periods of intervention due to the severity and complexity of the disorder (ASHA 2007) and intensive treatment is typically recommended to produce maximal outcomes (Rietvield et al., 2015). The cost of treating speech disorders (SD) including CAS is substantial. Slow and limited