Reciprocal White Matter Changes Associated With Copy Number Variation at 15q11.2 BP1-BP2: A Diffusion Tensor Imaging Study

Biol Psychiatry. 2019 Apr 1;85(7):563-572. doi: 10.1016/j.biopsych.2018.11.004. Epub 2018 Nov 19.


Background: The 15q11.2 BP1-BP2 cytogenetic region has been associated with learning and motor delays, autism, and schizophrenia. This region includes a gene that codes for the cytoplasmic FMR1 interacting protein 1 (CYFIP1). The CYFIP1 protein is involved in actin cytoskeletal dynamics and interacts with the fragile X mental retardation protein. Absence of fragile X mental retardation protein causes fragile X syndrome. Because abnormal white matter microstructure has been reported in both fragile X syndrome and psychiatric disorders, we looked at the impact of 15q11.2 BP1-BP2 dosage on white matter microstructure.

Methods: Combining a brain-wide voxel-based approach and a regional-based analysis, we analyzed diffusion tensor imaging data from healthy individuals with the deletion (n = 30), healthy individuals with the reciprocal duplication (n = 27), and IQ-matched control subjects with no large copy number variants (n = 19), recruited from a large genotyped population sample.

Results: We found global mirror effects (deletion > control > duplication) on fractional anisotropy. The deletion group showed widespread increased fractional anisotropy when compared with duplication. Regional analyses revealed a greater effect size in the posterior limb of the internal capsule and a tendency for decreased fractional anisotropy in duplication.

Conclusions: These results show a reciprocal effect of 15q11.2 BP1-BP2 on white matter microstructure, suggesting that reciprocal chromosomal imbalances may lead to opposite changes in brain structure. Findings in the deletion overlap with previous white matter differences reported in fragile X syndrome patients, suggesting common pathogenic mechanisms derived from disruptions of cytoplasmic CYFIP1-fragile X mental retardation protein complexes. Our data begin to identify specific components of the 15q11.2 BP1-BP2 phenotype and neurobiological mechanisms of potential relevance to the increased risk for disorder.

Keywords: 15q11.2 BP1-BP2; CYFIP1; Copy number variant; Diffusion tensor imaging; Fragile X syndrome; Genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Chromosome Aberrations*
  • Chromosome Deletion*
  • Chromosome Duplication*
  • Chromosomes, Human, Pair 15
  • DNA Copy Number Variations*
  • Diffusion Tensor Imaging
  • Female
  • Humans
  • Intellectual Disability*
  • Male
  • Middle Aged
  • White Matter / diagnostic imaging
  • White Matter / pathology*
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • CYFIP1 protein, human

Supplementary concepts

  • Duplication 15q11-q13 Syndrome