Simons Variation in Individuals Project: Characterizing the Phenotype of 16p11.2 Duplication Syndrome

Background:  Twin and family studies suggest that genetic factors are important in the development of ASD although it is also clear that these influences are complex.  Much past work in this field has been marred by inconsistent diagnostic methodology and poorly defined subject populations making it challenging to link particular genes to clinical subtypes.  While the exact incidence of ASD in individuals with 16p11.2 duplication is unknown, ASD and ASD-like features appear to be more prevalent in these individuals than in the general population. Increased incidence of ADHD has been reported in individuals with 16p11.2 duplication (Shinawi et al. 2009). There are also reports of increased incidence of psychiatric disorders, particularly schizophrenia (McCarthy et al. 2009, Levinson et al. 2011). Recent reports have highlighted issues of underweight (Jaquemont et al. 2011). In addition, there have been reports of specific neurological findings in these individuals (Horev et al. 2011, Bedoyan et al. 2010). Simons VIP is characterizing the phenotype of this disorder by studying over 100 individuals with this recurrent genetic disorder. 

Objectives:  To characterize the phenotype of the 16p11.2 duplication syndrome.

Methods:  Subjects are recruited from across the United States through the Simons VIP Connect website, and they travel to the clinical sites for a 2-3 day research visit.  All consenting participants with a documented duplication in 16p11.2 (29,557,497-30,107,356 bp) receive a comprehensive diagnostic assessment including an Autism Diagnostic Observation Schedule (ADOS), a DISC (Diagnostic Interview Schedule for Children), cognitive, language, behavioral and adaptive skills assessments.  The Autism Diagnostic Interview – Revised (ADI-R) is administered when SRS, SCQ or ADOS scores are elevated or there is a clinician concern for ASD.  Comprehensive medical information is obtained from participant/family report, and is also extracted from medical records.

Results:  To date, we have enrolled 65 individuals (from 29 families) with a 16p11.2 duplication.  The first 17 children with the duplication are included in this interim analysis.  Within the duplication sample, 8 are male.  Individuals range in age from 6 months to 14 years, and have a mean FSIQ of 73 (SD = 22.1).  Three individuals received a research diagnosis of an ASD.  In addition, a number of probands (n=4) met criteria on either ADOS or ADI, but not both measures, and so did not meet full research criteria for an ASD.  The most common diagnoses are Language Disorders (n = 7) and Intellectual Disability (n = 2).  Other common diagnoses include Borderline Intellectual Functioning (n=4), Phonological Disorder (n=2), and Disruptive Behavior Disorders/ODD (n=2).  Four individuals received no neurodevelopmental diagnosis.

Conclusions:  Among individuals with a 16p11.2 duplication, co-morbid diagnosis was common, with 7 (41%) participants receiving one or more neurodevelopmental diagnoses.  Several individuals have a language delay.  Further analysis will be conducted to fully characterize the phenotype of individuals with a 16p11.2 duplication.