The Phenotype of 16p11.2 Microdeletion and Microduplication

Background: Autism Spectrum Disorders (ASD) are neurodevelopmental disorders known to have a strong genetic basis.  Two recent papers described microdeletions and microduplications on chromosome 16 (16p11.2) in large samples of children previously diagnosed with ASD (Weiss et al, 2008; Kumar et al, 2008).  This de novo mutation seemed to account for approximately 1% of cases of ASD (Weiss et al, 2008) but the phenotypic spectrum of 16p11.2 cases has not been well described.     

Objectives: Describe the cognitive and behavioral phenotype of a group of 12 children (aged 2-18 years) from a hospital population diagnosed with microdeletions and microduplications at 16p11.2. 

Methods: A convenience sample of 12 families participated in the study and have completed a phenotyping battery consisting of standardized measures of cognitive ability, adaptive skills, and behavioral functioning, including the ADOS and ADI. Blood samples were drawn from each participating family member for DNA and RNA isolation as well as cell line creation. Additional measures were completed with other family members including the Family History Interview for participating parents and measures of adaptive skills and behavioral functioning for participating siblings.

Results: Four probands met criteria for ASD on both the ADOS and ADI. An additional two probands met ASD criterion on the ADOS but not the ADI, and another three probands met ASD criterion on the ADI but not the ADOS.  Thus, 9 of 12 probands met criterion for ASD on at least the ADOS or ADI. Nonverbal intelligence scores (NVIQ) ranged from standard scores of <49 (<1st percentile) to 131 (98th percentile) (Mean = 81; median = 81). Verbal intelligence scores (VIQ) ranged from <49 (<1st percentile) to 111 (77th percentile). (mean = 80, median = 85). 

The majority of children exhibited language delay, with eight probands acquiring single words at or after age 24 months and nine acquiring phrases at or after age 33 months.  There was reduced reporting of regression and increased reporting of high activity level similar to that described by Weiss et al.(2008).  

Conclusions: To the best of our knowledge, we have behaviorally phenotyped the largest group of children with the recently described 16p11.2 microdeletion/duplication. We found that children with the 16p11.2 microdeletion/duplication have an extremely varied phenotype.  Seventy-five percent of our population meet criterion for ASD on either the ADOS or ADI, or both, as well as when based on clinical impression. In addition, cognitive, adaptive and behavioral profiles are extremely varied.  Larger studies will be needed to fully characterize these children. We continue to recruit subjects and analyze results.