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

Abstract

BackgroundThe 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.MethodsCombining 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.ResultsWe 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.ConclusionsThese 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.

Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature

“…The CYFIP1 protein interacts with the fragile X mental retardation protein (the absence of which causes fragile X syndrome). A very recent imaging study of 15q11.2 BP1-BP2 deletion carriers 38 found abnormal white matter microstructure similar to that previously reported in fragile X syndrome, suggesting a role of CYFIP1 in the 15q11.2 deletion phenotype. A study 39 of neurons derived from patients with the 15q11.2 BP1-BP2 deletion showed abnormalities of dendritic spine formation.…”

“…ID and language delays are found in greater than two-thirds of cases, along with autism, behavioral problems, poor coordination, ataxia, and/or congenital anomalies. Psychiatric findings can include schizophrenia, oppositional defiant disorder, OCD, and dyslexia 38,41 . However, within the clinical setting most diagnosed cases have not been systematically evaluated with comprehensive clinical, medical, and behavioral assessments.…”

Neuropsychiatric copy number variants exert shared effects on human brain structure

“…Deletions and duplications at the 16p11.2, and to a lesser extent 22q11.2, loci affect global and regional brain volumes in opposite directions. This is also observed for cortical thickness (CT) and white matter (DTI) in deletions and duplications of the 15q11.2 BP1-BP2 locus 17,19 . Moreover, neuroanatomical alterations associated with 16p11.2 and 22q11.2 show overlap with those observed in idiopathic ASD and SZ 10,[13][14][15]17 .…”

“…They have shown robust effects on total and regional brain volumes e.g. 22q11.2 10,12 , 16p11.2 BP4-5 [13][14][15] , and 15q11.2 [16][17][18][19] . Deletions and duplications at the 16p11.2, and to a lesser extent 22q11.2, loci affect global and regional brain volumes in opposite directions.…”

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…In the 16p11.2 hemideletion mouse, there are pronounced sexspecific changes in males with increased FA in medial fiber tracts, especially in those proximal to the striatum, which correlate with gene expression patterns associated with neurite outgrowth and the mitogen-activated protein kinase (MAPK) pathway (Kumar et al, 2018). Furthermore, patients with deletions and duplications in the 15q11.2 chromosomal region present abnormalities in white matter architecture and brain structure (Silva et al, 2018;Stefansson et al, 2014;Ulfarsson et al, 2017;Vanlerberghe et al, 2015). Finally, genetic variations in the CNTNAP2 gene in humans have been associated with ASDs (Peñ agarikano and Geschwind, 2012), and KO of this gene in mice leads to reduced FC and aberrant white matter morphology (Liska et al, 2018;Zerbi et al, 2018).…”