Search
Close
Search
Advanced Search
Search Menu
AI Discovery Assistant

Abstract

Background: Schizophrenia (SZ) is a severe mental disorder with heritability estimated at ~80%. Genetic variants in contactin-associated protein-like 2 (CNTNAP2) have been reported in SZ. This gene is critically involved in normal neuronal synchronization and myelin production. Deletions in this gene would therefore be expected to impact white matter (WM) integrity. Compromised WM integrity has been implicated in SZ and may also be a heritable biomarker. In order to help characterize the genetic components of WM changes in SZ, we examined 2 carriers of a large heterozygous deletion in CNTNAP2 with discordant clinical phenotypes.

Methods: A 59-year-old female proband who met DSM-IV criteria for a diagnosis of schizoaffective disorder (depressed subtype), her clinically unaffected 90-year-old father, and 4 unrelated nonpsychiatric controls completed a diffusion kurtosis imaging protocol on a Siemens 3T system. Human-induced pluripotent stem cell (hiPSC) lines from skin biopsies of both carriers were generated and differentiated in vitro to oligodendrocytes.

Results: The fractional anisotropy (FA) and radial kurtosis (RK) were reduced, and the radial diffusivity (RD) was increased in the corona radiata and the genu of the corpus callosum (CC) in the proband compared with the father and controls. The clinically unaffected father closely resembled the controls in the genu of CC but differed from them in the uncinate fasciculus and internal capsule. In the whole-brain WM analysis, the FA and RK were reduced, and the RD was increased, in both the proband and the father compared with the controls, more substantially in the proband than in the father. Preliminary results from the in vitro differentiation suggest defective differentiation of patient-derived hiPSCs to oligodendrocyte precursor cells in the proband only.

Conclusion: These preliminary data suggest that WM integrity is compromised in both carriers, possibly due to a demyelinating process that may be associated with this specific mutation. More severe and widespread demyelination is present in the clinically affected proband than in the unaffected carrier father, suggesting that additional WM changes may be associated with SZ, possibly independent of this mutation. These findings complement the molecular and cellular phenotypes of the hiPSC neural cells derived from these carriers and support the role of brain imaging in helping to elucidate objectively measurable neuroanatomic phenotypic consequences of genetic variant susceptibility. This is one of the first studies to combine neuroimaging and hiPSC-based observations in carriers of the same mutation with discordant phenotypes, demonstrating the utility of both approaches in understanding pleiotropic clinical effects.

This content is only available as a PDF.
© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]
Topic:
Issue Section:
Abstracts > Posters (Saturday)
You do not currently have access to this article.
Download all slides