Analysis of Cognitive Performance, Social Functioning, and Body Mass Index As Quantitative Rather Than Dichotomous Traits in Individuals with Deletion 16p11.2

Background: The recurrent deletion 16p11.2 is the second most common pathogenic copy number variant identified among individuals with neurodevelopmental disorders. It was initially identified in subjects with autism and/or intellectual disability (ID) and subsequently associated with macrocephaly, obesity, seizures, speech and motor delays, congenital anomalies, and paroxysmal kinesigenic dyskinesia. Deletion carriers show substantial clinical heterogeneity, including apparently normal individuals, an observation often interpreted as evidence of incomplete penetrance.

Objectives: To evaluate in a quantitative manner the impact of deletion 16p11.2 on autism features, social functioning, cognitive abilities, and body mass index.

Methods: We studied 30 individuals with de novo del 16p11.2 from the Simons Variation in Individuals Project and their non-carrier parents (n=58) and siblings (n=19). We examined parent reports from the Social Responsiveness Scale (SRS), a quantitative scale that evaluates social awareness, reciprocal social communication, social information processing, and social anxiety, resulting in a T-score ranging from 30 (highly sociable) to 90 (severe social impairment) with a mean of 50 and a standard deviation (SD) of 10. SRS scores are highly heritable, commonly unrelated to intelligence quotient (IQ), and continuously distributed in the general population. We also evaluated full-scale IQ (FSIQ), a quantitative measure with a mean of 100 and a SD of 15, and body mass index (BMI), a proxy for human body fat based on an individual’s weight and height.

Results: Within this group, 32% of probands met full criteria for autism spectrum disorders using categorical diagnostic tools (ADI-R and ADOS). For the SRS, the mean T-score for probands was 71.9 compared to 46.8 in parents, and 44.7 in siblings. Moreover, scores in probands correlate with paternal scores (Spearman: rho (20) = .56, p = 0.1). Therefore, this quantitative trait revealed a 2.2 SD shift of mean SRS scores of probands relative to unaffected intrafamilial controls (p=4.44x10^-16). These results are very similar to those obtained using FSIQ to assess cognitive functioning in this subset of cases: 16.6% met a categorical diagnostic criteria for ID (FSIQ ≤70); however, if viewed as a quantitative trait, FSIQ was 1.8 SD lower in probands compared to their parents (p=6.66x10^-16) with a significant correlation between proband and maternal scores (Spearman: rho (29) = .43, p = .01). Finally, proband BMI z-scores were found to be 0.74 SD higher than parental scores and positively correlated with paternal BMI (Spearman: rho (24) = .55, p= .005).

Conclusions: By using continuous, quantitative traits such as FSIQ, SRS, and BMI scores to compare probands with their unaffected, non-carrier relatives, rather than using categorical variables such as DSM diagnoses or qualitative, dichotomous traits (i.e., normal vs. abnormal), we showed that parent-reported social behavior, cognitive function, and BMI are significantly impacted in a deleterious fashion among children with deletion 16p11.2 when compared to non-carrier relatives. These data may be more consistent with phenotypic heterogeneity related to genetic/family background rather than evidence of incomplete penetrance.