Update on DSM 5 and the Genomics of ASD Peter Szatmari MD Offord Centre for Child Studies, McMaster University and McMaster Children s Hospital Financial Disclosure The Canadian Institutes of Health Research Autism Speaks Sinneave Family Foundation Genome Canada Royalties from Guildford Press No other sources of funding (stocks, industry etc) Objectives Outline recent progress in identifying genetic variants associated with ASD Clinical implications of genetic testing Discuss our current understanding of ASD Review IV Proposals for DSM 5 Review evidence for those changes Outline some challenges and opportunities as DSM 5 becomes the accepted standard in the field of diagnosis 1
Autism Spectrum Disorder An heterogeneous spectrum disorder involving deficits in 3 domains of function Social communication deficits 0.6 % to 1% prevalence 4 to 1 sex ratio, more females with severe ID Strict autism Spectrum Changing epidemiology; more non-autism ASD Changing epidemiology; less frequent ID Increasing prevalence due to better case finding medical comorbidities 25-40% Diagnostic substitution occurring 4 Family Studies Retrospective studies; Original estimates for autism; 5% Based on ASD; 9% Baby Sibs studies (prospective design) risk to sib is 18% Relative risk is roughly 20 (based on population prevalence of 1%) Twin Studies Twin studies; traits in general population vs diagnosed twins Older studies of ASD twins; MZ vs DZ=.65 vs.05 Hallmeyer et al 2011; MZ vs DZ concordance Males.58 vs.21 Females.60 vs. 27 Greater role for shared environmental factors (55%) than genetic (37%) 2
The Search For Genetic Variants ASD in single gene disorders (SGD) ASD and large chromosomal abnormalities Rare genetic variants; Copy Number Variants (CNV), Kelleher III R.J and Bear M.F (2008) Cell 135, October 31, 2008 391 cytogenetically-visible breakpoints in autism Source: http://projects.tcag.ca/autism/ 1 2 3 4 5 6 7 8 9 10 11 12 13 Breakpoints Translocation (n=126) Deletion (n=128) Inversion (n=37) Duplication (n=100) 14 15 16 17 18 19 20 21 22 X Y 3
The Rare Variant Hypothesis Some single gene disorders; TS, FraX, NF, etc (5%) Some chromosomal abnormalities; spread throughout the genome (5%) Reduced fertility and lack of FH suggest new mutations that are rare Copy Number Variants are an example of rare genomic variants What are Copy Number Variants (CNV s)? Variations in DNA segments >1kb; Deletions, duplications, others Rare or common; inherited from parents or arise de novo? If CNV overlaps a gene expressed in brain, AND it disrupts the function of that gene (crosses and exon), AND it is not seen in controls, it could lead to ASD Copy Number Variation (CNV) Deletion Duplication CNV refers to DNA segments for which copy number differences have been observed in the comparison of two or more genomes Slide courtesy of Dr. C. Marshall Lee and Scherer, Expert Reviews in Mol. Med. 2010 4
Slide courtesy of Julie Cohen, ScM, CGC, Kennedy Krieger Institute CNV burden in known ASD and/or ID genes All CNVs DELs only Curated lists of implicated loci: - 110 ASD - 196 Intellectual disability (ID) Population attributable risk (PAR) stage 1, ASD= 6.8% (n= 1,406 cases) stage 2, ASD= 4.5% (n= 775 cases) stage 1, ID= 1.6% stage 2, ID= 0.8% stage 1 + 2, ASD + ID =~155 cases in total Enrichment of genic-dels in the combined known ASD and ID loci in cases vs. controls (2.1 fold, 95% CI = 1.25-3.40, P = 5.4x 10-4 ) 14 Genes in which CNV s have been replicated Neuroligin 3 and 4 Neurexin Shank2 and Shank3 Contactin associated protein 2 PTCHD1 Large region on chromosome 16p11 New ones reported each week! Each one seen in <1% of cases Range of effects; linked in common networks, 5
Where Do We Go Now? ASD is a common disorder caused by rare genetic variants Disorder is highly heterogeneous; each family has its own private variant (almost) Common variants have not been ruled out Smaller and smaller CNV (indels) Rare sequence variants/mutations Province of Ontario Neurodevelopmental Disorder (POND) Network Diagnostic yields projected in the genetic evaluation of ASDs High-resolution chromosome studies (5%) Fragile X and MECP2 (5%) PTEN (3% if head circumference > 2.5 SDs) Other SGD s (10%) acgh beyond what would be detected by chromosomal analysis (10%) Range of penetrance values per CNV Total=30-40%? 6
CNV s for Etiologic Diagnosis CNV s as a cause of my child s ASD? Most of these CNV s are not inherited and so explains lack of family history No assignment of guilt But little knowledge of how CNV causes autism; inherited vs de novo Lack of CNV/phenotype correlation Summary Genetic testing for ASD is here Usefulness of testing depends on testing for what? Maybe helpful for etiologic testing Much more research is needed to increase yield of genetic variants and especially to ensure that testing does more good than harm DSM Classification and Diagnostic Systems for Autism Not included in DSM II Work of Rutter and Wing; autism based on social and communication deficits and repetitive behavior 1980; Rutter and DSM-III; strict, narrow, restrictive 1987; Wing and DSM-III-R; broad and over-inclusive DSM-IV in 1994; finally acceptable sensitivity but perhaps low specificity (resulting in over diagnosis) DSM 5 to be official in 2013; what will it look like? 7
DSM-IV Dx of Autism Three symptom domains: Reciprocal social interaction, Verbal and NV communication Repetitive behaviours 4 items in each domain; 12 in total Above cut-off in all three; 2, 1, 1 >6 in total Age of onset <3years DSM IV PDD Sub-types DSM IV (APA, 1994) : Spectrum of disorders called the Pervasive Developmental Disorders (PDDs) Autistic Disorder Asperger syndrome PDD-NOS Rett's disorder Childhood Disintegrative Disorder Problems with DSM IV Criteria could be better in several ways; Over-inclusive; subjects without ASD given that diagnosis (especially PDDNOS) Clinicians cannot apply the criteria to distinguish autism from Asperger from PDDNOS Subtypes do not differ on variables such as outcome, cause or treatment needs Triad better conceptualized as dyad 8
What is DSM IV s understanding of the Core Phenotypes? Autistic triad ; Impairments in social reciprocity, In V and NV communication and Preference for engaging in repetitive, stereotyped behaviours Empirical Measurement models A univariate phenotype; the Social Responsiveness Scale (Frazier et al 2010; Constantino et al 2004; Bolte et al 2008) Multivariate; a series of FA studies of the ADI-R; 2-6 dimensions (Tadevosyan-Leyfer et al 2003; Georgiades et al 2007) Studies of twins from general population and with ASD (Dworzynskis et al 2009; Happe et al 2006) Social impairment and Communication impairment are the same construct but distinct from RSB s Summary of Problems with DSM IV Classification System Leads to over-diagnosis Two not three core phenotypes (social-communication and RSB s) Difference between subtypes represent differences in severity; and differentiation among sub-types cannot be made reliably No clinically meaningful differences between sub-types 9
DSM 5 Neurodevelopmental Disorder Working Group A sub-group works on autism/asd Experts in diagnosis, measurement, clinical expression (different than DSM IV) Review of the literature, reports for public discussion, field trials Preliminary and final criteria for ASD Report from DSM V (Jan 2011) A single diagnosis (ASD) to replace Autism, PDD-NOS and Asperger disorder. No evidence that sub-types have a different outcome or etiology Need to reduce over-diagnosis Make criteria more developmentally equivalent Age of onset not so specific Proposal for DSM 5 Two dimensions; social-communication and repetitive stereotyped behavior A spectrum of severity from requiring support to requiring very substantial support Can add clinical specifiers (as yet undefined) Age of onset is early childhood 10
Social Communication (all 3) 1. Deficits in social-emotional reciprocity; 2. Deficits in nonverbal communicative behaviors used for social interaction; 3. Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers); Repetitive Sensory & Motor Behaviour (2 of 4) 1. Stereotyped or repetitive speech, motor movements, or use of objects; 2. Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change; 3. Highly restricted, fixated interests that are abnormal in intensity or focus; 4. Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment; Proposed multidimensional model mild impairment severe impairment Social Communication Inflexible Language & Behaviour 11
Summary of Changes Key distinction for clinical practice is ASD/non-ASD One disorder (ASD) Two dimensions, each person with ASD occupies a unique place on the dimensions Age of onset changed from <3years to early childhood Clinical specifiers; language, IQ, etc Empirical Evaluation of DSM 5 Mandy et al 2012; confirms two dimension model Mattila et al; misses some cases with Asperger and HFA Frazier et al 2012; confirms two dimension model; criteria reduce over-diagnosis but miss some cases of Asperger, female ASD These were published before the modification of DSM 5 criteria Jan 2011 Evaluation of DSM V More accurate than DSM IV It s parsimonious, based on a thorough review of evidence and consensus among experts But does it really capture the heterogeneity and hence the complexity of ASD? 12
Advantages of Parsimony Less need for expert clinicians More rapid access to clinical services People with AS and PDDNOS will not be denied services reserved for people with autism No longer diagnostic odysseys to decide what type of ASD a child has (Autism, AS or PDDNOS) The terms PDDNOS disappears CAN-A-GEN At HSC, Steve Scherer, Andrew Paterson, Wendy Roberts, John Vincent, Michelle Lui, Jennifer Skaug, Dalila Pinto, Christian Marshall At McMaster, Christine Chrysler, Carolyn Russell, Irene O Conner, Ann Thompson, Jeremy Goldberg, Eric Duku, Stelios Georgiades, Mark Woodbury- Smith, Bill Mahoney Lonnie Zwaigenbaum (U of Alberta), Bridget Fernandez (Memorial), Susan Bryson (IWK, Dalhousie) 13