Effects of sex chromosome aneuploidies on brain development: Evidence from neuroimaging studies

Abstract

Variation in the number of sex chromosomes is a relatively common genetic condition, affecting as many as 1/400 individuals. The sex chromosome aneuploidies (SCAs) are associated with characteristic behavioral and cognitive phenotypes, although the degree to which specific individuals are affected can fall within a wide range. Understanding the effects of different dosages of sex chromosome genes on brain development may help to understand the basis for functional differences in affected individuals. It may also be informative regarding how sex chromosomes contribute to typical sexual differentiation. Studies of 47,XXY males make up the bulk of the current literature of neuroimaging studies in individuals with supernumerary sex chromosomes, with a few small studies or case reports of the other SCAs. Findings in 47,XXY males typically include decreased gray and white matter volumes, with most pronounced effects in the frontal and temporal lobes. Functional studies have shown evidence of decreased lateralization. Although the hypogonadism typically found in 47,XXY males may contribute to the decreased brain volume, the observation that 47,XXX females also show decreased brain volume in the presence of normal pubertal maturation suggests a possible direct dosage effect of X chromosome genes. Additional X chromosomes, such as in 49,XXXXY males, are associated with more markedly decreased brain volume and increased incidence of white matter hyperintensities. The limited data regarding effects of having two Y chromosomes (47,XYY) do not find significant differences in brain volume, although there are some reports of increased head size.Keywords sex chromosome; aneuploidy; neuroimaging; brain; development Sex is the single greatest discriminating morphometric factor in biology [Ropers and Hamel, 2005]. Overall brain size in humans is robustly dimorphic, with males having an approximately 10% greater volume. Sexual dimorphism of the developing brain is especially pertinent for child psychiatry, given that nearly all neuropsychiatric disorders of childhood demonstrate striking sex differences with respect to age of onset, prevalence, and symptom patterns [Giedd et al., 1997]. Factors giving rise to sexual dimorphism may thus also act as risk factors or protective agents for neurodevelopmental disorders, and understanding the development of sexual dimorphism may provide insights into the pathogenesis of neurodevelopmental disorders. NIH Public Access Author ManuscriptDev Disabil Res Rev. Author manuscript; available in PMC 2010 December 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBiological contributions to sex differences include sex differences in gonadal secretions that affect the brain and direct effects of the sex chromosome genes. The relative ease of manipulating hormone levels in animal models has led to a preponderance of literature and discussion about the effects of hormones on the brain. However, a growing body of literature [Arnold, 2004] is now suggesting that differ...

Socio‐economic factors affect mortality in 47,XYY syndrome—A comparison with the background population and Klinefelter syndrome

“…During school age, learning disabilities requiring educational intervention are present in approximately 50% and are as responsive to intervention as they are in children with normal chromosomes [Gotz et al, 1999;Ratcliffe, 1999]. Hyperactivity, distractibility, and temper tantrums have been reported and may affect their school performance [Lenroot et al, 2009]. Certain personality traits, such as infantilism, lack of emotional control, and increased impulsiveness after emotional stimulation have been described [Noel et al, 1974].…”

Structural and numerical changes of chromosome X in patients with esophageal atresia

“…The observation that 47,XXX females also have decreased brain volume in the presence of normal pubertal maturation suggests a possible direct dosage effect of X-chromosomal genes. 41 Two EA candidate genes MID1 and FANCB do not escape X-inactivation, although there is a X-inactivation preference for the X chromosome that contains the mutated allele in Fanconi anemia. 24 Other genes that escape XCI could perhaps cause the gastrointestinal anomalies found in our cohort.…”

The Causes and Consequences of Aneuploidy in Eukaryotic Cells

“…There are only few types of aneuploidies that are compatible with survival. Various aneuploidies of sex chromosomes usually do not interfere with the survival and manifest with rather mild growth alterations, mild mental disability and infertility [7]. The effect of sex chromosome abnormalities is relatively low and does not interfere with viability due to the small genetic contribution of chromosome Y and due to X chromosome silencing via an epigenetic mediated pathway [8].…”