Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2

Radiology. 2018 Jan;286(1):217-226. doi: 10.1148/radiol.2017162934. Epub 2017 Aug 8.


Purpose To identify developmental neuroradiologic findings in a large cohort of carriers who have deletion and duplication at 16p11.2 (one of the most common genetic causes of autism spectrum disorder [ASD]) and assess how these features are associated with behavioral and cognitive outcomes. Materials and Methods Seventy-nine carriers of a deletion at 16p11.2 (referred to as deletion carriers; age range, 1-48 years; mean age, 12.3 years; 42 male patients), 79 carriers of a duplication at 16p11.2 (referred to as duplication carriers; age range, 1-63 years; mean age, 24.8 years; 43 male patients), 64 unaffected family members (referred to as familial noncarriers; age range, 1-46 years; mean age, 11.7 years; 31 male participants), and 109 population control participants (age range, 6-64 years; mean age, 25.5 years; 64 male participants) were enrolled in this cross-sectional study. Participants underwent structural magnetic resonance (MR) imaging and completed cognitive and behavioral tests. MR images were reviewed for development-related abnormalities by neuroradiologists. Differences in frequency were assessed with a Fisher exact test corrected for multiple comparisons. Unsupervised machine learning was used to cluster radiologic features and an association between clusters and cognitive and behavioral scores from IQ testing, and parental measures of development were tested by using analysis of covariance. Volumetric analysis with automated segmentation was used to confirm radiologic interpretation. Results For deletion carriers, the most prominent features were dysmorphic and thicker corpora callosa compared with familial noncarriers and population control participants (16%; P < .001 and P < .001, respectively) and a greater likelihood of cerebellar tonsillar ectopia (30.7%; P < .002 and P < .001, respectively) and Chiari I malformations (9.3%; P < .299 and P < .002, respectively). For duplication carriers, the most salient findings compared with familial noncarriers and population control participants were reciprocally thinner corpora callosa (18.6%; P < .003 and P < .001, respectively), decreased white matter volume (22.9%; P < .001, and P < .001, respectively), and increased ventricular volume (24.3%; P < .001 and P < .001, respectively). By comparing cognitive assessments to imaging findings, the presence of any imaging feature associated with deletion carriers indicated worse daily living, communication, and social skills compared with deletion carriers without any radiologic abnormalities (P < .005, P < .002, and P < .004, respectively). For the duplication carriers, presence of decreased white matter, callosal volume, and/or increased ventricle size was associated with decreased full-scale and verbal IQ scores compared with duplication carriers without these findings (P < .007 and P < .004, respectively). Conclusion In two genetically related cohorts at high risk for ASD, reciprocal neuroanatomic abnormalities were found and determined to be associated with cognitive and behavioral impairments. © RSNA, 2017 Online supplemental material is available for this article.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder* / diagnostic imaging
  • Autistic Disorder* / epidemiology
  • Autistic Disorder* / genetics
  • Brain / diagnostic imaging*
  • Brain / pathology
  • Child
  • Child, Preschool
  • Chromosome Deletion*
  • Chromosome Disorders* / diagnostic imaging
  • Chromosome Disorders* / epidemiology
  • Chromosome Disorders* / genetics
  • Chromosomes, Human, Pair 16 / genetics
  • Cluster Analysis
  • Cross-Sectional Studies
  • DNA Copy Number Variations / genetics*
  • Female
  • Gene Deletion
  • Gene Duplication / genetics
  • Humans
  • Infant
  • Intellectual Disability* / diagnostic imaging
  • Intellectual Disability* / epidemiology
  • Intellectual Disability* / genetics
  • Magnetic Resonance Imaging / methods*
  • Male
  • Middle Aged
  • Young Adult

Supplementary concepts

  • 16p11.2 Deletion Syndrome