Neuroimaging Findings in 16p11.2 Deletion and Duplication Carriers

Background: As a group, the reciprocal 593 kb 16p11.2 deletions and duplications are some of the most common genetic causes associated with autism, schizophrenia and other neurodevelopmental disorders. The Simons Variation in Individuals Project (Simons VIP) has enrolled nearly 200 individuals with a 16p11.2 deletion or duplication many of whom have undergone structural and functional brain MR imaging and a comprehensive phenotypic assessment including a neuropsychological battery, interviews, and clinical evaluations.  Herein we report findings from a qualitative assessment of the MRI visible neuroanatomical differences present in the 16p11.2 deletion/duplication population.

Objectives: We hypothesize that individuals with 16p11.2 deletions/duplications will have structural changes visible on brain MRI, and that many of these findings will differ between 16p11.2 duplications and deletions.

Methods: We reviewed high quality MRI scans of 66 deletion and 56 duplication carriers and 44 non-carrier family members using a structured review process targeting developmental anomalies. The reported findings represent the initial review of the project's lead board certified neuroradiologist blinded to genetic status. Frequencies of abnormalities were compared between deletion and duplication carriers and non-carrier family members using the Chi-squared test for independence, and significant findings surviving Bonferroni correction for multiple comparisons are presented.

Results: Several aberrant anatomical features were identified in patients with 16p11.2 deletion/duplications. When compared to non-carriers, 16p11.2 duplication patients showed an increased frequency of thin or dysmorphic corpora callosa (22% of patients, 2% of controls, p < 0.01), increased frequency of enlarged ventricles (25% of patients, 2% of controls, p<0.01), and decreased white matter volume (33% in patients, 5% of controls, p<0.001). When compared to non-carriers, 16p11.2 deletion patients showed an increased frequency of skull base malformations characterized by platybasia, posterior angulation of the dens and crowding of the posterior fossa (41% of patients, 2.5% of controls, p<0.001) and an increased frequency of cerebellar tonsillar ectopia (28% of patients, 5% of controls, p<0.001). These skull base malformations can lead to Chiari I malformations and syringomyelia. Trending toward significance is the comparison of small pituitary size between deletion carriers and non-carriers (17% of deletions, 2.6% of controls, uncorrected p=0.028).  The deletions and duplications each separately thus present with a different subset of significant changes in brain development in comparison to non-carriers, highlighting the differences between these two genomic syndromes. Work is ongoing to correlate these anatomical phenotypes with functional imaging data, cognitive, behavioral and other clinical findings.

Conclusions: This is the first study of its depth of clinical characterization and sample size to systematically identify brain imaging abnormalities in a cohort of genetically defined individuals with susceptibility to autism.  There is a significant incidence of pituitary abnormalities and skull base abnormalities in the deletion patients that have clear clinical consequences including presence of Chiari I malformations. Our ongoing work to link cognitive data and functional imaging data with these anatomical changes will likely provide important additional insights into correlates between neuroanatomy and behavior.