Brain Structure and Quantitative Trait Shifts in 16p11.2 De Novo Deletions Relative to Non-Carrier Siblings

Background: The 16p11.2 deletion syndrome is a copy number variation (CNV) resulting in the deletion of 29 genes. It may be inherited or occur as a de novoevent, and has been associated with a range of neurodevelopmental and neuropsychiatric disorders (NDPSs) including autism spectrum disorders (ASD) (Moreno-De-Luca 2013; Maillard 2014). The 16p11.2 deletion is found in up to 1% of individuals with ASD, and is associated with increased total intracranial, gray, and white matter volumes as well as volumetric increases in the cerebellum, thalamus, fusiform and superior temporal gyri, precuneus, and insula (Qureshi 2014, Maillard 2014). Recent studies indicate that the 16p11.2 deletions carriers exhibit a ‘shift’ (delta between the non-carrier sibling) toward greater impairment on a range of phenotypic traits (Moreno-De-Luca 2014). It remains unclear, however, whether similar shifts, relative to non-carrier relatives, also apply to key brain structures.

Objectives: Here, we aim (1) to replicate findings that reveal phenotypic shifts in 16p11.2 deletions relative to non-carrier siblings on a variety of quantitative phenotypic traits; (2) to examine whether deletions exhibit volumetric shifts in brain regions relative to non-carrier siblings; (3) examine whether observed phenotypic shifts in deletions may be explained by corresponding shifts in brain volumes.

Methods: Fifteen families with 16p11.2 de-novo deletions (12.6±4 years) and non-carrier siblings (12.1±5.6 years) from the Simons Variation in Individuals Project (Simons VIP Consortium, 2012) were included in this study. Verbal and non-verbal IQ, CBCL-Internalizing and CBCL-Externalizing, SRS, Purdue Pegboard Test scores and high resolution brain MRIs were examined. Volumes of cortical and subcortical brain structures were computed using FreeSurfer, adjusted for age, sex and BMI and were normalized by each subject’s total brain volume.

Results: As noted previously, phenotypic scores of deletion were shifted toward greater impairment relative to their siblings (percentages of families out of 15 and P-values are within parenthesis) in the following domains: verbal IQ (87%, 0.006), non-verbal IQ (80%, 0.02), CBCL Internalizing (87%, 0.006), SRS (100%, 6E-5) and Pegboard (87%, 0.006); see Figure 1. In 11 of 15 families (73%), deletions had larger total brain volume compared to their siblings. But in all 15 families (P<6E-5) deletions’ cortical gray matter volume when calculated as a percentage of total brain was smaller compared to siblings (Figure 2). Deletions’ ventricles were negatively correlated with both verbal (P<0.02) and non-verbal (P<0.004) IQ; corpus callosum volume was positively correlated with CBCL-Internalizing (P<0.03). In non-carrier siblings, thalamic volume correlated positively to non-verbal-IQ (P<0.02), and the ventral-DC was negatively correlated to CBCL-Internalizing (P<0.03) and CBCL-Externalizing (P<0.02). The shift in ventricular volume predicted shift in verbal-IQ (P<0.04) and non-verbal-IQ (P<0.02).

Conclusions: This study shows that de novo 16p11.2 deletions show deleterious phenotypic shifts relative to non-carrier siblings and shifts in brain volume of key structures implicated in ASD and other NDPDs. We show that shifts in certain phenotypes can be mirrored by shifts in brain structures. These findings highlight the importance of considering family background when examining the deleterious impact of the 16p11.2 and other CNV syndromes that are implicated in NDNPs.