Genomic Imprinting Effects of the X Chromosome on Brain Morphology

Abstract

There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X-chromosome on physical and cognitive characteristics in human, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X-chromosome. Of the young girls with TS, 23 inherited their X-chromosome from their mother (Xm) and 17 from their father (Xp). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with Xp demonstrated thicker cortex than those with Xm in the temporal regions bilaterally, while Xm individuals showed bilateral enlargement of gray matter volume in the superior frontal regions in comparison to Xp. These data suggest the existence of imprinting effects of the X-chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X-chromosome.

Sex differences in amygdala shape: Insights from Turner syndrome

“…Thus, in this sample, we are able to examine the effects of absence of one complete X chromosome on amygdala structure before the administration of exogenous estrogen. The sample used in this study overlaps with previously published work [Hong et al, ; Lepage et al, ]. The local Institutional Review Board of the Stanford University School of Medicine approved this study and informed written consent was obtained from a legal guardian for all participants.…”

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

“…Most of the studies analyzing parent-of-origin effects in TS, report a predominance of the maternal X, largely due to the non-viability of the karyotype 45,Y and a slight preferential loss of paternal sex chromosomes (66, 67,68,69,70,71). Several studies analyzed whether X-linked imprinting effects might be associated with distinct phenotypical features, with conflicting results (72,73,74). Lack of statistical power to detect subtle differences explains part of the observed heterogeneity (Table 4).…”

Sex differences in cancer mechanisms

“…Male embryos inherit only the maternal X, while female embryos inherit both a maternal and paternal X [132]. Differences in the phenotype of XO girls who inherit a paternal (X p ) vs. a maternal (X m ) Xchromosome, suggest that X-chromosome imprinting does impact development, particularly in the brain [132,134]. Intriguingly, one study found a trend towards increased brain volume in X m O girls, compared to X p O girls [134], suggesting potential roles of X imprinted genes on regulating growth.…”