Autism Spectrum Disorders
John N. Constantino MD William Greenleaf Eliot Division of Child and Adolescent Psychiatry Intellectual and Developmental Disabilities Research Center
Disclosure of Interests
• Industry Consulting: – Roche Pharmaceuticals
• Stock Equity: None • Royalties: Western Psychological
Services The Social Responsiveness Scale (SRS-2)
• Research Support: – NICHD, – U.S. CDC – U.S. Administration for Children and Families
• Subsidy of Clinical/Research “Hybrids”: Missouri Autism Centers of Excellence
1981-1984
DSM-V Autism Spectrum Disorder Must meet criteria 1, 2, and 3: 1. Clinically significant, persistent deficits in social communication and interactions, as manifest by all of the following: a. Marked deficits in nonverbal and verbal communication used for social interaction: b. Lack of social reciprocity; c. Failure to develop and maintain peer relationships appropriate to developmental level 2. Restricted, repetitive patterns of behavior, interests, and activities, as manifested by at least TWO of the following: a. Stereotyped motor or verbal behaviors, or unusual sensory behaviors b. Excessive adherence to routines and ritualized patterns of behavior c. Restricted, fixated interests 3. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)
National survey, 7,461 participants
Recurrence Rates and Inherited Transmission in Autism n ~ 4M
MZ concordance: DZ concordance: Non-twin sib recurrence: General population risk
“SPORADIC” (60%)
90+% 20% 18% 1%
FAMILIAL (40%)
De novo (germline)
Common var. (polygenic)
Rare inherited
Rare inherited
Danish Study (1.5M) JAMA Pediatr. 2013 Oct;167(10):947-53. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. Grønborg TK1, Schendel DE, Parner ET.
Swedish Study (2.0M) JAMA. 2014 May 7;311(17):1770-7. The familial risk of autism. Sandin S1, Lichtenstein P2, Kuja-Halkola R2, Larsson H2, Hultman CM2, Reichenberg A3.
JAMA. 2014 Sep 17;312(11):1154-5. doi: 10.1001/jama.2014.9841. Recurrence rates in autism spectrum disorders. Constantino JN.
Constantino, Todorov, Geschwind et al. (2013)
-Transmission through unaffected parents -If additive, accounts for 60% of causal variance. -High proportion of population-attributablerisk for autism likely polygenic
Full Siblings
Number of Subjects Recurrence Rate
IAN 4,832 .095
ACE 132 .114
Maternal Half Siblings IAN ACE 619 41 .052 .073
Paternal Half Siblings IAN ACE 55 31 (.000) (.032)
July 2014
The distribution of social and cognitive impairments in a population of children with a specific genetically-defined syndrome is often wide, and for 22q11.2 and 16p11.2 manifest correlations with “genetic background” distributions indexed by variation in the subjects’ parents HIGHLY-PENETRANT MUTATIONS RESULT IN PREDICTABLE PATHOLOGICAL SHIFT FROM WHAT WOULD BE “EXPECTED” ON THE BASIS OF AN INDIVIDUAL’S GENETIC BACKGROUND
The Social Responsiveness Scale Quantifies presence and severity of social impairment within the autism spectrum and differentiates it from that which occurs in other disorders Ages: 2.5 years through adulthood Administration Time: 15 to 20 minutes Format: Parent and/or teacher and/or other adult informant rating scale Norms: Total Score; Scores for DSM-5 Subscales
Wave 2
Life Course, 4-20 yrs
ASD probands Unaff. sibs of ASD probands
Constantino et al., manuscript in preparation
n=1,600
Constantino et al., Arch Gen Psychiatry 2003
h2 =.80
n=3,807
Ronald et al., JAACAP 2006
n=8,094
Skuse et al., JAACAP 2009
h2=.77
Small shifts in diagnostic threshold can result in large changes in prevalence
Constantino et al. (2006) Am J Psychiatry 163(2):294-6
ANOVA (brothers) F=16.2; df=2,188; p