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

Richard S Lee,Joseph Bressler,Andrew Zabel,Carole Samango-Sprouse,Andrea Gropman,Henri M Garrison-Desany,Patricia Lasutschinkow,Sophia Q Song,Jenny L Carey

doi:10.1186/s13148-021-01123-4

Abstract

BackgroundEqual 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.ResultsTwo 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.ConclusionsBoys 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.

Highlights

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
The mean age of the twentysix participants with 47,XXY for whom Behavior Rating Inventory of Executive Function (BRIEF) was available was significantly higher than the group of eleven participants with 49,XXXXY
Mean averages for all of the BRIEF Composite scales were significantly higher than the test value of T = 50 in the 49,XXXXY group (T = 62.0 to 66.6, P < 0.01 for all comparisons using the Student’s T-test), suggesting a significantly higher level of parent-reported executive dysfunction in these individuals

Summary

Introduction

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

Methods

Results

Discussion

Conclusion