DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study

Abstract

Background Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. Results Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. Conclusions Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

Clinical, Cognitive and Neurodevelopmental Profile in Tetrasomies and Pentasomies: A Systematic Review

“…[ 18 ]. Some authors hypothesised that the overall features of affected patients were due to the abnormal dosage of genes beyond what is normally guaranteed between males and females by X-inactivation of the second X chromosome in females [ 21 ]. It is known that clinical, neurocognitive, and developmental characteristics worsen with extra X chromosomes [ 37 ].…”

“…It is known that clinical, neurocognitive, and developmental characteristics worsen with extra X chromosomes [ 37 ]. Gropman and colleagues [ 10 ] studied clinical variability and neurodevelopmental findings in 20 patients affected by 49, XXXXY and attributed the variability of their profile to skewed inactivation of additional chromosomes or mosaicism and methylation abnormalities [ 21 ]. According to Lee et al [ 21 ], methylation levels of multiple CpGs in androgen receptor (AR) monoamine oxidase A (MAO-A) genes are associated with differences in both internalizing and externalizing behaviour in boys with 49, XXXXY as compared with neurotypical boys.…”

“…In addition, over 42% of adolescents had clinically elevated working memory [ 19 ]. Lee et al [ 21 ] conducted a pilot study to understand both the association between methylation on X chromosome genes and behavioural aspects in 47, XXY and 49, XXXXY patients and the possible effect of hormonal replacement therapy (HRT). Parents of patients completed the CBCL and BRIEF questionnaires, and experts did not observe significant differences in scores on either questionnaire between 46, XY and 47, XXY groups, though higher scores related to executive dysfunction, internalizing, externalizing, and total behavioural problems were observed in the 49, XXXXY group [ 21 ].…”

“…Lee et al [ 21 ] conducted a pilot study to understand both the association between methylation on X chromosome genes and behavioural aspects in 47, XXY and 49, XXXXY patients and the possible effect of hormonal replacement therapy (HRT). Parents of patients completed the CBCL and BRIEF questionnaires, and experts did not observe significant differences in scores on either questionnaire between 46, XY and 47, XXY groups, though higher scores related to executive dysfunction, internalizing, externalizing, and total behavioural problems were observed in the 49, XXXXY group [ 21 ]. The three extra X chromosomes in this cohort of patients were associated with important effects on gene expression and behaviour, as compared to patients with just one extra X chromosome (47, XXY) [ 21 ].…”

“…Parents of patients completed the CBCL and BRIEF questionnaires, and experts did not observe significant differences in scores on either questionnaire between 46, XY and 47, XXY groups, though higher scores related to executive dysfunction, internalizing, externalizing, and total behavioural problems were observed in the 49, XXXXY group [ 21 ]. The three extra X chromosomes in this cohort of patients were associated with important effects on gene expression and behaviour, as compared to patients with just one extra X chromosome (47, XXY) [ 21 ]. After DNA methylation analysis of a small selective group of X chromosome genes (conducted on a saliva sample), the authors concluded that methylation levels of multiple CpGs in MAO A were associated with externalizing behaviour problems, while in AR they were associated with Brief Regulation Index score [ 21 ].…”