Randall 1
Clarie Randall
Dr. Bert Ely
Bio 303 H: Genetics
1 November 2014
Sex Chromosome Aneuploidies: Genetic Backgrounds and Neurological Implications
In every thousand births, 1-2 children are born with an extra X sex chromosome. In males, this condition is known as Klinefelter syndrome (47,XXY karyotype) and in females, Trisomy X (47,XXX karyotype). These children are at higher risks for communication deficits during development, are more likely to have impairments in both fine and gross motor skills, often show qualities of shyness, social ineptitudes and anxiety, difficulties in forming and keeping relationships, problems with regulating emotions, and struggle with reading social signals such as tone of voice and gaze direction (Bishop et al. 2011). These traits are similar to traits characteristicin children with autism spectrum disorders (ASD), which has led to research comparing X chromosome aneuploidies and ASD symptomatology, a step in connecting neuroscience and genetics research.
Aneuploidy is a type of chromosome number abnormality; one type of aneuploidy in humans results from one extra chromosome – this condition is called trisomy and is not restricted to solely sex chromosomes (however, that is what the topic of this paper explores). In fact, “the most common type of viable human aneuploid is Down syndrome… by far the most common type of Down syndrome is trisomy 21, caused by nondisjunction of chromosome 21 in a parent who is chromosomally normal. Like any mechanism, chromosome disjunction is error prone and sometimes produces aneuploid gametes” (Griffiths et al. 2000). In this paper, aneuploidies of the 47th chromosome, specifically the addition of an extra X chromosome, are explored in relation to autistic tendencies and the overarching umbrella of the field of genetics.
In one study from the Netherlands conductedwithin the last year by Rijn et al. (2014), the phenotypic characteristics of children diagnosed with ASD were compared to those with a triple X chromosome disorder. Both boys and girls were used as subjects in this study, which is novel because most studies involving X chromosome aneuploidies only include data from boys with Klinefelter syndrome (KS), leading to very little research into the Trisomy X condition. Thus, this study did not only contribute to the diversity of research on the topic, but took sex into account in order to observe if there were phenotypic developmental differences between males and females with triple X chromosome conditions.
This study used the Autism Diagnostic Interview Revised Edition (ADI-R), Social Responsiveness Scale (SRS), Social Anxiety Scale (SAS), and Social Skills Rating System (SSRS) to compare three identified sub-groups (children with an extra X chromosome, children with ASD, and non-clinical controls). The ADI-R provides a cut-off score to determine if a patient has ASD; this measurement is determined based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Statistical Classification of Diseases and Health-related Problems (ICD-10) in determining an autism diagnosis. The SRS analyzes the test-taker’s social awareness, cognition, communication, motivation, and autistic mannerisms; the SAS measures social, intellectual, and physical skills as well as appearance and social desirability; the SSRS measures cooperative, assertive, self-control, and responsibility social skills (Rijn et al. 2014).
Children with an extra X chromosome scored significantly lower in all domains of the ADI-R (social interactions, communication, stereotyped behaviors) compared to children with ASD diagnoses, indicating that the children with a triple X chromosome syndrome are less demonstrative of autistic traits (Fig. 1). The analysis of the SRS scores showed that extra X chromosome children fell in-between the two other groups, showing significantly higher levels of autistic traits than the non-clinical controls and significantly lower levels of autistic traits than the group of children diagnosed with ASD. Furthermore, among the children with an extra X chromosome, those that demonstrated autism symptoms early on in development showed higher SRS scores (stronger autism traits) while those that did not demonstrate early symptoms of autism only showed stronger autistic traits when compared to the control group (Rijn et al. 2014).
Fig. 1: Scores (mean and standard deviation) on the subscales of the Social Responsiveness Scale in the sub-groups of children with an extra X chromosome, children with ASD, and the non-clinical controls.
Analysis of the scores on the SAS showed that children with an extra X chromosome had higher levels of social anxiety on all sub-scales compared to both the non-clinical controls and the group of children with ASD(Fig. 2). Additionally, there was not a significant difference in the scores of children with an extra X chromosome who demonstrated early autism symptoms in development versus those who did not (Rijn et al. 2014).
Fig. 2: Scores (mean and standard deviation) on the subscales of the Social Anxiety Scale in the sub-groups of children with an extra X chromosome, children with ASD, and the non-clinical controls.
Scores on the SSRS showed that the group of children with an extra X chromosome again fell in-between the two other sub-groups; the children in the extra X group had significantly higher scores (better social skills) than the children with ASD but significantly lower scores (worse social skills) than the group of non-clinical controls on all subscales of the SSRS (Fig. 3). Furthermore, children in the extra X group with early autism symptoms showed higher levels of impairment in social functioning compared to the control group versusthe group of children with an extra X chromosome but without early autism symptoms (Rijn et al. 2014).
Fig. 3: Scores (mean and standard deviation) on the subscales of the Social Skills Rating System in the sub-groups of children with an extra X chromosome, children with ASD, and the non-clinical controls.
When analyzing differences based on sex among children with an extra X chromosome, a lack of variance in test scores was found on all but one subscale, “Cooperation” within the Social Skills Rating System, which showed significant group-by-sex interaction in favor of girls with an extra X chromosome (Rijn et al. 2014).
Overall, this study found that there are many similarities in children with an extra X chromosome aneuploidy and those with autism spectrum disorder, including additional difficulties cooperating with others, being assertive in social situations, taking social responsibilities, and exerting self-control in social situations. Differences in the two groups were most evident when comparing levels of social anxiety: children with an extra X chromosome showed higher levels of social anxiety compared to the group of typically-developing children while the children with ASD did not (excluding the subcategory of physical ability).
It has been found that both social cognition and social skills are heavily influenced by different genetic factors, with the possibility that the genetics influence on social skills is as high as 68% (Scourfield et al. 1999).Additionally, aneuploidies involving an extra X chromosome are specifically noted for further genetics-based research due to the fact that a high density of genes on the X chromosome has been found to be essential for neural development (Zechner et al. 2001) Finally, research into the genetics of chromosome 47 aneuploidies should be further explored due to the findings from Rijn et al. (2014) that“indicate that Klinefelter syndrome and Trisomy X can be associated with an increased vulnerability for autistic symptomatology”.
In that same vein of interest, a study from the United States conducted in 2012 examined a similar concept to that in the Rijn et al. study (2014), except through a broader scope: ASD and impairments in language domains were examined in young people with different kinds of sex chromosome aneuploidies (X and Y chromosome aneuploidies of trisomy, tetrasomy, and pentasomy varieties).It has been hypothesized that the human X chromosome contains approximately 1,400 genes (XuDisteche 2006) and around 40% of these genes (885 total genes identified thus far) are also expressed in the brain (Ropers & Hamel 2005). Therefore, excess doses of the genes on X and Y chromosomes“may contribute to some of the language and social impairments reported for X/Y-aneuploidies” (Lee et al. 2012). This study attempted to analyze that hypothesis.
The Wechsler Abbreviated Scale of Intelligence (WASI) and Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) which measure verbal IQ (Vocabulary and Similarities subtests) and performance IQ (Block Design and Matrix Reasoning subtests), Children’s Communication Checklist (CCC-2) which measures structural language (Speech, Syntax, Semantics, and Coherence subscales), pragmatic language (Initiation, Scripted Language, Context, and Nonverbal Communication subscales), and ASD-associated behavioral difficulties (Social Relations and Interests subscales), and Social Responsiveness Scale were all utilized in this study. The CCC-2 scores were used to construct the Social Interaction Difference Index, which shows the relationship between a child’s social and structural language skills (Lee et al. 2012).
This study found that both X and Y chromosome aneuploidies are linked to lower verbal IQ scores and pragmatic and structural language abilities as well as increased reported ASD symptomatology (Fig. 4). Additionally, the X chromosome appeared to be linked to lower scores in structural language compared to pragmatic language while the Y chromosome shows the opposite trend (lower pragmatic language scores vs. structural language scores); these scores were accounted for with the Social Interaction Difference Index, in which “positive scores indicate stronger pragmatic/social skills than structural language abilities, characteristic of language impairments, whereas negative scores indicate stronger structural language than pragmatic/social skills, characteristic of ASD”. Based on this study’s data, the X chromosome appeared to be associated with a higher rate of language impairment, while the Y chromosome appeared to be associated with a higher rate of ASD symptomatology (Lee et al. 2012).
Furthermore, this study implies that increasing the number of X chromosomes (trisomy X, tetrasomy X, pentasomy X, i.e.) is related to increased language impairments, specifically structural vs. pragmatic language skills, while an increasing number of Y chromosomes in the genome is linked to increased difficulty with pragmatic language. This study also supports the claims from the first study (Rijn et al. 2014) that sex chromosome aneuploidies are associated with impaired social skills and “heightened social difficulties” (Lee et al. 2012).
Fig. 4: Scores earned by each participant sub-divided by genotype. Solid line indicates mean value for each group. Reported scores are: (a) WASI VIQ, (c) CCC-2 Structural Language, (e) CCC-2 Social Interaction Difference Index, (b) WASI PIQ, (d) CCC-2 Pragmatic Language, and (f) SRS raw score.
A third paper from 2010 shines new light on the genetics research surrounding sex chromosome aneuploidies by examining the source of the X chromosome (parental origin) in relation to the psychopathology (study of mental disorders) of those with Klinefelter syndrome, particularly looking at autistic traits in younger patients and schizotypal traits in older patients (Bruining et al. 2010). For the purposes of this paper, only the results and discussion involving the younger group tested for ASD will be included.
The ADI-R was used to measure autistic symptomatology in the younger group (all children and adolescents); these scores were then separated by parental origin of the X chromosome and compared to the control group (Bruining et al. 2010).
Fig. 5: Average ADI-R domain scores of control group and the group of younger subjects with Klinefelter syndrome divided by parental origin of X chromosome (maternal vs. paternal).
Fig. 6: Average ADI-R label scores for each domain of control group and the group of younger subjects with Klinefelter syndrome divided by parental origin of X chromosome (maternal vs. paternal).
* indicates p < 0.05.
The results of this study show that the parental origin of the additional X chromosome did exhibit an effect on the level of autistic symptomatology in the young subjects with Klinefelter syndrome(Fig. 5).The study found that the overall multivariate effects of each group (maternal, paternal, control) indicated that parental origin had an effect on the score of autistic symptomatology in the subjects. Additionally, there were significant differences for individual trait scores within the ADI-R (subscales) (Fig. 6). However, “significant differences in autistic traits were not consistent. One was associated with maternal origin and others with paternal origin” (Bruining et al. 2010).
While this study made some interesting observations, it is still not clear if parental origin affects the “complex gene dosage and inactivation patterns in KS”. However, other research conducted on the brains of mice has found that there is a possibility that the parental origins of additional X chromosomes in cases of aneuploidy have different effects on the functioning of the brain (Gregg et al. 2010). Conclusively, there could be a linkage between parental origin of an extra X chromosome and differences in ASD profiles, but more research is necessary to thoroughly examine these relationships. From this study, however, Klinefelter syndrome appears to be an insightful avenue for continued research on the connection between X chromosome-linked imprinting and psychopathology (Bruining et al. 2010).
In summary, the findings of Rijn et al. (2014), Lee et al. (2012), and Bruining et al. (2010) have begun to propose probable connections between autism spectrum disorders and related psychopathologies and X chromosome aneuploidies in the human genome. Specifically, there is a marked connection found between autistic symptomatology, Trisomy X, and Klinefelter syndrome (Rijn et al. 2014, Lee et al. 2012).
Also, the Bruining et al. (2010) study has provided a pathway for further research into the genetics and possible hereditary links in additional X chromosome aneuploidies. Further research should work to find more effects of different origins of the extra X chromosomes as that may lead to identifying linkages between what causes ASD and disorders like Trisomy X and Klinefelter syndrome.
Works Cited
Bishop D, et al. (2011) Autism, language and communication in children with sex chromosome trisomies. Archives of Disease in Childhood 10:954–959 doi:10.1136/adc.2009.179747.
Bruining H, RijnS, SwaabH, Giltay J, KatesW, J.H. Kas M, EngelandH, de SonnevilleL (2010) The Parent-of-Origin of the Extra X Chromosome May Differentially Affect Psychopathology in Klinefelter Syndrome. Biological Psychiatry 68.12:1156-1162 doi: 10.1016/j.biopsych.2010.08.034
Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, Dulac C (2010) High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science 329:643– 648doi: 10.1126/science.1190830
Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. Aneuploidy. Available from:
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