University of South Carolina Scholar Commons Theses and Dissertations Spring 2020 The Utility of Whole Exome Sequencing in Patients With Intellectual Disability and Developmental Delay as a First-Tier Diagnostic Testing Strategy Ellen Richardson Follow this and additional works at: https://scholarcommons.sc.edu/etd Part of the Genetics and Genomics Commons Recommended Citation Richardson, E.(2020). The Utility of Whole Exome Sequencing in Patients With Intellectual Disability and Developmental Delay as a First-Tier Diagnostic Testing Strategy. (Master's thesis). Retrieved from https://scholarcommons.sc.edu/etd/5717 This Open Access Thesis is brought to you by Scholar Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. THE UTILITY OF WHOLE EXOME SEQUENCING IN PATIENTS WITH INTELLECTUAL DISABILITY AND DEVELOPMENTAL DELAY AS A FIRST-TIER DIAGNOSTIC TESTING STRATEGY by Ellen Richardson Bachelor of Science University of South Carolina, 2011 Master of Science University of South Carolina, 2014 Submitted in Partial Fulfillment of the Requirements For the Degree of Master of Science in Genetic Counseling School of Medicine University of South Carolina 2020 Accepted by: Kellie Walden, Director of Thesis Mike Friez, Reader Ken Corning, Reader Cheryl L. Addy, Vice Provost and Dean of the Graduate School © Copyright by Ellen Richardson, 2020 All Rights Reserved. ii Acknowledgements I would like to acknowledge the dedication and support of my thesis committee during this process. Without the support of Kellie Walden, Mike Friez, and Ken Corning this project would not have come to fruition. My thesis advisor, Kellie Walden for numerous phone calls, emails, and her valuable insight. I would like to thank the Greenwood Genetic Center for support and access to patient data. Wilma Sims at the University of South Carolina, for her help with data analysis. Thank you to all of the patients included in this study for trusting Greenwood Genetic Center with your care, and allowing researchers to use your story to make a difference for future patients. iii Abstract The purpose of this study is to evaluate the diagnostic utility of whole exome sequencing (WES) in patients with intellectual disability (ID) or developmental delay (DD), and to determine which patients may be the best candidates for WES as a first-tier diagnostic test. The diagnostic and clinical utility of WES has emerged to be greater than that of karyotype and chromosomal microarray for patients with ID or DD of unknown etiology, which are currently recommended as first-tier diagnostic tests for these patients. The emergence of next generation sequencing has led to more rapid identification of rare and novel genetic disorders. Diagnosis of such disorders can impact medical management and save money. The value of this study lies in identifying which patients with ID or DD are more likely to receive a diagnosis via WES and therefore should be offered WES as a first-tier diagnostic test. This study is a retrospective review of electronic medical records of patients with ID/DD seen at the Greenwood Genetic Center (GGC) who have had WES. Patients were categorized into diagnosed, undiagnosed, or uncertain categories. Comparisons between patients were made based on delay types, dysmorphic features, birth defects, and comorbid conditions. Neither delay type, number of delays, age of diagnosis, or birth defects had a significant effect on likelihood of diagnosis. Patients with neurological features, tone differences, or eye movement disorders were significantly more likely to obtain a diagnosis by WES. Changes to medical management in diagnosed patients include referrals to new specialists, adjustments in medication iv prescriptions, identification of contraindicated medications, and referrals to specialty clinics specific to disease. These data suggest that WES should be considered as a first- tier test in any patient with ID or DD, and WES may have a higher diagnostic utility for those with underlying neurological disorders. v Table of Contents Acknowledgements ............................................................................................................ iii Abstract .............................................................................................................................. vi List of Figures ................................................................................................................... vii List of Abbreviations ....................................................................................................... viii Chapter 1: Background ........................................................................................................1 Chapter 2: The Utility of Whole Exome Sequencing in Patients with Intellectual Disability and Developmental Delay as a First-tier Diagnostic Testing Strategy ....11 Chapter 3: Conclusions ......................................................................................................38 References ..........................................................................................................................40 Appendix A: Features Included in Each Category ............................................................46 vi List of Figures Figure 2.1 Methods by Which Cases Were Filtered to Assess for Features ......................16 Figure 2.2 Overall Diagnostic Rate ...................................................................................20 Figure 2.3 Mean Age at Date of WES Report ...................................................................20 Figure 2.4 Average IQ per WES Result Category .............................................................21 Figure 2.5 Number of Delays per Patient Population ........................................................22 Figure 2.6 Prevalence of Delay in Patient Population .......................................................22 Figure 2.7 Odds Ratios for Delay Type .............................................................................23 Figure 2.8 Prevalence of Dysmorphic Features .................................................................24 Figure 2.9 Odds Ratios for Dysmorphic Features .............................................................24 Figure 2.10 Prevalence of Birth Defects ............................................................................25 Figure 2.11 Odds Ratios for Birth Defects ........................................................................25 Figure 2.12 Prevalence of Comorbid Conditions ..............................................................26 Figure 2.13 Odds Ratios for Comorbid Conditions ...........................................................26 Figure 2.14 Prevalence of Neurological Features ..............................................................27 Figure 2.15 Odds Ratios for Neurological Features ..........................................................27 Figure 2.16 Secondary and Incidental Findings Revealed by WES ..................................28 vii List of Abbreviations ACMG..................................................................... American College of Medical Genetics ADHD .................................................................. Attention Deficit Hyperactivity Disorder CMA ............................................................................................ Chromosomal Microarray DD .......................................................................................................Developmental Delay FXS ....................................................................................................... Fragile X Syndrome GDD ........................................................................................ Global Developmental Delay GGC ........................................................................................... Greenwood Genetic Center ID ........................................................................................................ Intellectual Disability IQ ..........................................................................................................Intellectual Quotient LD .......................................................................................................... Learning Disability NDD ...................................................................................... Neurodevelopmental Disorder NGS......................................................................................... Next Generation Sequencing NSV..................................................................................................No Significant Variants P/LP....................................................................................... Pathogenic/Likely Pathogenic VUS................................................................................. Variant of Uncertain Significance WES ............................................................................................ Whole Exome Sequencing WGS .......................................................................................... Whole Genome Sequencing viii Chapter 1 Background Clinical Diagnosis of Intellectual Disability (ID) and Developmental Delay (DD) The term developmental delay (DD) is frequently used to describe a child that is failing to meet milestones typical to a developing child his or her age. Four common categories of DD include: 1) cognitive,