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