Of these, only full-scale IQ did (p = 0.02). Overall, the data showed a strong effect of large rare genic de novo CNVs on the presence or absence of an ASD diagnosis, but did not support either IQ or find more ASD severity as useful predictors for probands carrying these risk variants (Figure 3C). We did observe a trend toward more gene-rich de novo CNVs in females (Figure 2) and found females to be less vulnerable to the reduction in IQ associated with rare de novo CNVs. We next investigated whether individuals

with recurrent CNVs at 16p11.2 or 7q11.23 showed distinctive behavioral or cognitive profiles compared with probands who were not carrying rare de novo events. For each proband carrying a de novo CNV at 16p11.2 or 7q11.23, five other probands were selected as controls based on hierarchical matching criteria: first age, then sex, genetic distance, ascertainment site, and whether the sample was from a quartet or trio. Our primary Selleck Tofacitinib analysis focused on four variables: full-scale IQ, categorical diagnosis, severity of autism, and body mass index (BMI) (Table 2), with the latter motivated by multiple reports that 16p11.2 deletions contribute to obesity (Bijlsma et al., 2009 and Walters et al., 2010). We then pursued a broader exploratory

study of additional phenotypic variables, ten of which are presented in Table 2 with the remainder in Table S5. We found that probands carrying a 16p11.2 or 7q11.23 de novo CNV were indistinguishable from the larger group with regard to IQ, ASD severity, or categorical autism diagnosis (Table 2). However, we did find a relationship between body weight and 16p11.2 deletions and duplications. When we treated copy number as an ordinal variable (one, two, and three copies) and used the matched controls as the diploid sample, BMI diminished as 16p11.2 copy number increased (estimated β = −3.1kg/m2

for each extra copy, p = 0.02). The extensive phenotypic data available on the SSC sample constitute a great resource for fine-grained analyses of genotype-phenotype relationships. In the current study, the limiting factor with regard to recurrent de novo CNVs was the small sample size, even for 16p11.2 duplications and deletions. Nonetheless, we undertook to an exploratory analysis of a range of phenotypic features and found several that yielded significant p values. While none would survive correction for multiple comparisons, we report them here in the interest of generating hypotheses for future studies (Table 2 and Table S5). For example, individuals with 16p11.2 duplications had higher hyperactivity scores compared to matched control probands, while probands carrying 7q11.23 duplications showed significantly more behavioral problems (Aberrant Behavior Checklist total), but less severe social and communication impairment during ADOS administration.