A Practical Update on Genetic Testing, Diagnosis, and Next Generation Treatment Approaches for Persons with Developmental Brain Disorders

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1 A Practical Update on Genetic Testing, Diagnosis, and Next Generation Treatment Approaches for Persons with Developmental Brain Disorders Brenda Finucane, MS, LGC Geisinger Autism & Developmental Medicine Institute Lewisburg, Pennsylvania 1 Disclosures Consultant, Board of Directors National Fragile X Foundation Consultant, LabCorp Geisinger Autism & Developmental Medicine Institute Lewisburg, PA 2 1

2 Objectives Genetic versus behavioral diagnoses: how do they fit together? Current status of genetic diagnostic testing Emerging perspectives on developmental brain disorders Leveraging genetic diagnoses to inform support plans Current resources and future directions Developmental Disabilities Also known as: Intellectual and developmental disabilities Neurodevelopmental disorders Developmental disabilities are a group of conditions due to an impairment in physical, learning, language, or behavior areas. These conditions begin during the developmental period, may impact day-to-day functioning, and usually last throughout a person s lifetime. Centers for Disease Control and Prevention, 2018 Prevalence: 1 in 6 children has a developmental disability (CDC, 2015) 4 2

3 Developmental Disabilities Intellectual disability (ID) Autism spectrum Disorder (ASD) Cerebral Palsy Specific language impairment Attention deficit disorder Learning disability + many others 5 Autism Spectrum Disorder (ASD) complex disorder of brain development characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviors Autism Speaks, 2015 Prevalence: 1 in 59 children has ASD (CDC, 2018) 6 3

4 Intellectual Disability (ID) Intellectual disability: characterized by significant limitations in both intellectual functioning and in adaptive behavior, which covers many everyday social and practical skills. This disability originates before the age of 18. American Association on Intellectual and Developmental Disabilities, 2015 Prevalence: 1 in 91 children has ID (CDC, 2006) 7 Developmental Disabilities ASD, ID, CP, etc.: symptom constellations with numerous underlying causes Often co-occur: ~50% with ASD have ID / learning difficulties ~40% with ID diagnosed with psychiatric disorder ~40% with CP have ID Clinically-defined symptom diagnoses for which there are numerous underlying causes 8 4

5 Psychiatric Disorders Also known as: Mental health conditions Mental illnesses Mental illnesses are health conditions involving changes in thinking, emotion or behavior (or a combination of these). Mental illnesses are associated with distress and/or problems functioning in social, work or family activities. American Psychiatric Association, 2017 Prevalence: 1 in 5 adults has a mental health condition (NAMI, 2017) 9 Psychiatric Disorders childhood and adult-onset based on observed, recognizable patterns of human behavior described in the Diagnostic & Statistical Manual (DSM) clinical, symptom-based diagnoses: do not emphasize etiology not diagnosed using laboratory tests or imaging 10 5

6 Psychiatric Diagnoses OCD Autism Spectrum Disorder Impulse Control Disorder Symptoms versus Causes Etiology: Underlying cause Autism, ID, schizophrenia and other brain disorders: symptom-based clinical diagnoses for which there are numerous different etiologies Genetic and / or medical factors play a major role in the etiology of developmental brain dysfunction Advances in genetic testing have revealed shared underpinnings for distinct developmental and psychiatric clinical disorders 12 6

7 Developmental Brain Disorders (DBD) Wide range of developmental, neurological, and psychiatric conditions that overlap in symptoms and etiology Examples: Intellectual disability Autism spectrum disorder Epilepsy Schizophrenia Same genetic underpinnings result in different developmental and psychiatric diagnoses (ID, ASD, schizophrenia, etc.), even within the same family 13 Etiology Matters Genetic counseling for families to address reproductive concerns to alleviate guilt, misconceptions Anticipation of medical needs Insight into behavior, learning styles Syndrome-specific support organizations Targeted research and intervention 14 7

8 Genetic Disorders Prevalence: ~1 in 22 people has a genetic disorder Newborns: 3% have 1 or more significant congenital anomalies (differences at birth, more than just cosmetic) 20 30% of infant deaths due to genetic disorders >1200 genetic disorders include ID as a symptom Most people with DBD have not had a comprehensive genetic evaluation to try to determine the cause 15 Genetic testing in people with DBD Diagnostic testing Clinical testing (not research) Examples: microarray, fragile X analysis Identifies rare causative genomic variants (differences) with large effects on brain function Pharmacogenomics for medication response Tests for genomic variants affecting drug metabolism Primarily looking at genes expressed in the liver Limited clinical utility for psychotropic medications Lots of marketing, little evidence 16 8

9 Genetic testing in people with DBD Genome-wide association studies (GWAS) Research focus Additive small effects of common genomic variants Susceptibility variants (of small additive magnitude) 17 The Human Genome Genome: the entire set of genetic instructions found in a cell; the entirety of a person s genetic make-up Human genome ~20,000 genes National Human Genome Research Initiative (NHGRI)

10 Genetics Vocabulary DNA (deoxyribonucleic acid) contains the genetic information in a body s cells made up of 4 similar chemicals (A,G,C,T) that come in pairs and make up the DNA code Gene: specific section of DNA code that contains instructions for making body chemicals (proteins) Chromosome: a cell structure that contains numerous genes 19 Genetics Vocabulary Genomic variants (formerly mutations ): significant differences in the expected DNA code that can be inherited or occur for the first time in an individual Copy number variants (CNVs) Deletions, duplications: differences in the amount of chromosomal material Usually involve multiple genes Sequence variants Changes in the letters of the DNA code Single gene disorders 20 10

11 Genetics Vocabulary Syndrome ( running together ): recognizable pattern of features that repeatedly occurs Congenital: present at birth Dysmorphology: the study of structural differences, particularly birth defects Phenotype: observable characteristic(s) (physical, behavioral) related to the expression of a gene(s) 21 Medical Genetics a.k.a. Clinical Genetics Recognized medical specialty Healthcare teams include Clinical / Medical Geneticist Genetic Counselor AboutGeneticCounselors.com 22 11

12 Trends in Genetic / Genomic Testing Genetics moving out of the specialty clinic and into mainstream medicine Increase in number of clinically available genetic tests since completion of Human Genome Project Decreasing cost for genome sequencing Shift from genetics to genomics Websites Courses RESOURCES Amer College of Med Genetics genetics course: Nat l Society of Genetic Counselors online course on genomics: 12

13 Chromosomal Microarray Analysis Microarray: a tool for analyzing gene variation that consists of a small membrane or glass slide containing samples of many sections of genetic material arranged in a regular pattern Able to examine check for copy number variants (deletions, duplications) Ability to identify changes > than our ability to interpret them ( variants of uncertain significance ) Whole Exome / Genome Sequencing (WES, WGS) Laboratory tests that detect changes in the DNA code Powerful diagnostic tools Ability to identify changes >> than our ability to interpret them ( variants of uncertain significance ) WES available clinically and currently being used in evaluation of unexplained developmental and other disorders 13

14 Diagnostic Genetic Testing First line recommendations* for children with global developmental delay / ID / ASD of unknown cause: Fragile X (FMR1) DNA analysis Chromosomal microarray analysis Whole exome sequencing (WES) increasingly ordered in the evaluation of those with uninformative fragile X and microarray results (25 30% diagnostic yield) *American College of Medical Genetics and Genomics *American Academy of Pediatrics 27 Next Generation Diagnostics Chromosomal microarray, WES: dramatically increased diagnostic yield for rare genomic variants in developmental and psychiatric disorders Current evidence points to significant role of rare pathogenic copy number and sequence level variants with large effects on brain function Individually rare, collectively common Genomic background / common variants with small effects explain variable expressivity 28 14

15 22q11.2 Deletion Syndrome Previously known as. DiGeorge syndrome Absent thymus, hypocalcemia, cardiac Velocardiofacial syndrome (VCFS) Characteristic face, cardiac, cleft, LD Conotruncal Anomaly Face (CTAF) syndrome Cardiac, characteristic face 15

16 22q11.2 Deletion Syndrome Highly variable multiple congenital anomaly syndrome Common cause of LD, ID, psychiatric symptoms Males and females equally affected 1 in births Associated with microdeletion of 22q qDS: Characteristics Congenital heart defects Characteristic facial appearance Hypernasal voice Ear malformations Immune deficiency Feeding / swallowing problems Hypocalcemia Short stature (growth hormone deficiency) 16

17 22qDS: Cardiac Findings ~ 80% born with cardiac defects ranging from mild to severe Most common types: - Tetralogy of Fallot - Interrupted aortic arch - Truncus arteriosus - VSD 22qDS: Palate Problems 62% born with palate differences ranging from mild to severe 2%: cleft lip and palate 11%: cleft palate 14%: submucosal clefts 5%: bifid uvula 30%: velopharyngeal incompetence (VPI) 17

18 22qDS: Development 15% No significant speech delay 46% Borderline delay 39% Definite delay 20-40% have ID (usually mild) VIQ > PIQ in most children, less so in adults 60-80% normal IQ / learning disability 22qDS: Psychiatric / Behavioral Profile School age: ADD / ADHD Anxiety disorder Impulse control disorder OCD Autism spectrum disorder Depression (facial hypotonia?) 18

19 22qDS: Psychiatric / Behavioral Profile Adolescence / adulthood: Pulver et al., 1994: 29% with schizophrenia / schizoaffective disorder Papolos et al, % met criteria for bipolar spectrum disorders Bassett et al., 2005 schizophrenia in 25%, indistinguishable from that of other causes 22qDS: Neuropsychological Profile Strengths Verbal IQ Verbal Comprehension Rote Verbal Learning Rote Verbal Memory Initial Auditory Attention Simple Focused Attention Auditory Perception and Memory Word Reading Word Decoding 19

20 22qDS: Neuropsychological Profile Weaknesses Nonverbal processing Visuospatial skills Complex verbal memory Attention, working memory, executive functioning Motor functions Simple Focused Attention Visual-spatial memory Facial processing and recall 22qDS: Neuropsychological Profile Weaknesses Phonological processing Language processing Mathematics Reading comprehension Social skills Emotional functioning Adaptive functioning 20

21 22q11.2 Deletion Syndrome: Resources Geisinger 22q Developmental Clinic geisingeradmi.org The International 22q11.2 Foundation 22q.org 22q and You Center Children s Hospital of Philadelphia chop.edu/centers-programs/22q-and-you-center Targeted Therapeutics for Genetic Disorders Psychopharmacology: study of drug effects on mood, sensation, thinking, and behavior Traditionally, symptom-based approaches to pharmaceutical interventions for people with DBD Targeted therapeutics for genetic disorders: pharmaceutical treatments that address / correct underlying biochemical pathways 21

22 Age of Clinical Syndromes Primarily 1950s s Description of clinical genetic syndromes Emphasis on physical findings Clinically suspected, sometimes confirmed by lab tests Rare disorders, considered esoteric 43 Age of Gene Discovery 1980s - present Molecular mapping of clinical genetic syndromes New clinical syndromes described after laboratory discoveries Genotype-phenotype correlations Syndrome-specific support groups 22

23 Age of Molecular Mechanisms 2000s and beyond Human Genome Project Advances in laboratory technologies Gene sequencing, protein expression Elucidation of gene function and biochemical pathways Animal models of human genetic disease 45 Advocacy Organizations: Families as Partners 23

24 Targeted Treatments: A Tale of Two Syndromes Fragile X Tuberous sclerosis Fragile X Syndrome Most common known hereditary cause of ID and ASD Occurs in both males and females, males more commonly affected Diagnosed using highly accurate DNA testing Single gene disorder with well-described clinical profile Robust animal models Highly motivated and sophisticated national support organizations successfully lobby for research funding 24

25 Fragile X and Autism Majority of males and many females have symptoms consistent with autism spectrum disorder Fragile X: most common known single gene cause of autism ~ 1 in 20 children with ASD has fragile X as the underlying cause Just One Gene. 1991: FMR1 gene discovered Previously unknown genetic mechanism Complex inheritance pattern; gene changes cause wide range of effects from one generation to the next In fragile X syndrome, gene fails to produce Fragile X MR Protein (FMRP) FMRP expressed in brain prenatally and throughout life 25

26 FMRP and mglur Group I metabotropic glutamate receptors (mglur): involved in pathway that stimulates protein synthesis at neuronal synapses FMRP inhibits synaptic protein synthesis Two systems act in tandem to regulate production of neuronal proteins Without FMRP, mglur activity is increased: abnormal synaptic signaling and dendritic structure; learning / behavioral differences 51 Fragile X: Therapeutic Targets Focus on compounds that mimic FMRP function Preclinical studies showed reversal of neurologic deficits, phenotype rescue in fragile X animal models 26

27 Fragile X Clinical Trials : Several phase 2 and 3 clinical trials of drugs aimed at FMRP-related pathways Results failed to show significant benefit in humans Hand-wringing among families and investigators! Outcome measures? Placebo effect? Older age of participants? New round of clinical trials underway Fragile X Clinical Trials 27

28 Tuberous Sclerosis Complex (TSC) Well-described neurological condition Relatively common cause of ID, autism, epilepsy Very variable from one person to the next Multi-system involvement (brain, skin, kidneys, lungs) Causes growth of benign tumors, other physical signs in addition to DBD Tuberous Sclerosis Complex (TSC) Caused by mutations in TSC1 and TSC2 genes Genes normally produce a protein compound that regulates mtor mtor (mammalian target of rapamycin): protein involved in tumor cell division, blood vessel growth, and regulation of synaptic protein synthesis / signaling Mutations in TSC1 and TSC2 genes result in dysregulation of cell division and decreased synaptic protein synthesis 28

29 Targeted Pharmaceutical Treatment of TSC mtor inhibitor shown to reduce tumors in TSC mice 2010: FDA approves clinical use of mtor inhibitor to treat inoperable brain tumors in TSC 2012: FDA approves mtor inhibitor to shrink angiomyolipomas (benign kidney tumors) in TSC Topical rapamycin approved to treat skin tumors Additional human trials underway to determine effect of mtor inhibitors on autism, cognition, seizures Fragile X / Tuberous Sclerosis FXS and TSC: involve different genes, both disorders can cause autism and ID Both produce synaptic proteins that have opposite effects on synaptic protein synthesis (FXS: too much synthesis, TSC: too little synthesis) Targeted treatments with opposite effects rescued FXS and TSC animal models Breeding FXS mouse with TSC mouse resulted in unaffected offspring! 29

30 Tuberous Sclerosis 30

31 Angelman Syndrome Rett Syndrome 31

32 Age of Shared Pathways Emerging research collaborations across different genetic causes of brain disorders Many roads to a common end point: disease pathways intertwined at a molecular level Promising model for the study of autism, intellectual disability, and other DBD Family organizations and researchers as partners This is only the beginning.. Acknowledgements Neurodevelopmental Pediatrics Thomas D. Challman, MD Scott Myers, MD Nancy Eisenhauer, PA-C Kristen Douglass, PA-C Monisa Wagner, PA-C Lis Turner, CRNP Katie Oetjens, CRNP Psychology / Behavior Analysis Cora Taylor, PhD Heidi Fisher, PhD Barbara Haas-Givler, BCBA Matt Kinney, BCBA GeisingerADMI.org.and the many families who make our work possible Genetics Christa Lese Martin, PhD David H. Ledbetter, PhD Emily Palen, MS Juliann Savatt, MS Devin Shuman, MS Karen Wain, MS Speech-Language Pathology Marissa Mitchel, CCC-SLP Beth Petro, CCC-SLP Kristin Ellis, CCC-SLP All of Team ADMI! 64 32