Dataset Information

Patterns of psychopathology and cognition in sex chromosome aneuploidy.

ABSTRACT:

Background

Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase the risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally occurring model for studying X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology and (ii) the notable interindividual variation in psychopathology is related to co-occurring variation in cognitive ability.

Methods

We examined scores for 11 dimensions of psychopathology [Child/Adult Behavior Checklist (CBCL)] and general cognitive ability [full-scale IQ (FSIQ) from Wechsler tests] in 110 youth with varying SCAs (XXY = 41, XYY = 22, XXX = 27, XXYY = 20) and 131 typically developing controls (XX = 59, XY = 72).

Results

All SCAs were associated with elevated CBCL scores across several dimensions of psychopathology (two-sample t tests comparing the euploidic and aneuploidic groups [all |T| > 9, and p < 0.001]). Social and attentional functioning were particularly sensitive to the carriage of a supernumerary Y-chromosome. In particular, the XYY group evidenced significantly more social problems than both extra-X groups (Cohen's d effect size > 0.5, Bonferroni corrected p < .05). There was marked variability in CBCL scores within each SCA group, which generally correlated negatively with IQ, but most strongly so for social and attentional difficulties (standardized β, - 0.3). These correlations showed subtle differences as a function of the SCA group and CBCL scale.

Conclusions

There is domain-specific variation in psychopathology across SCA groups and domain-specific correlation between psychopathology and IQ within SCAs. These findings (i) help to tailor clinical assessment of this common and impactful family of genetic disorders and (ii) suggest that dosage abnormalities of X- and Y-linked genes impart somewhat distinct profiles of neuropsychiatric risk.

SUBMITTER: Rau S

PROVIDER: S-EPMC8903493 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Patterns of psychopathology and cognition in sex chromosome aneuploidy.

Rau Srishti S Whitman Ethan T ET Schauder Kimberly K Gogate Nikhita N Lee Nancy Raitano NR Kenworthy Lauren L Raznahan Armin A

Journal of neurodevelopmental disorders 20211215 1

<h4>Background</h4>Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase the risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally occurring model for studying X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology and (ii) the notable interindividual v ...[more]

PMID: 34911436

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Project description:ImportanceThe reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.ObjectivesTo determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls.Design, setting, and participantsThis cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023.ExposureGenomic identification of an additional X or Y chromosome.Main outcomes and measuresOutcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio.ResultsOf 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]).Conclusion and relevanceIn this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.

Project description:BackgroundThe discovery of differentially organized sex chromosome systems suggests that heteromorphic sex chromosomes evolved from a pair of homologous chromosomes. Whereas karyotypes are highly conserved in alethinophidian snakes, the degeneration status of the W chromosomes varies among species. The Z and W chromosomes are morphologically homomorphic in henophidian species, whereas in snakes belonging to caenophidian families the W chromosomes are highly degenerated. Snakes therefore are excellent animal models in which to study sex chromosome evolution. Herein, we investigated the differentiation processes for snake sex chromosomes using both coding and repetitive sequences. We analyzed phylogenetic relationships of CTNNB1 and WAC genes, localized to the centromeric and telomeric regions, respectively, of the long arms on snake sex chromosomes, and chromosome distribution of sex chromosome-linked repetitive sequences in several henophidian and caenophidian species.ResultsPartial or full-length coding sequences of CTNNB1 and WAC were identified for Z homologs of henophidian species from Tropidophiidae, Boidae, Cylindrophiidae, Xenopeltidae, and Pythonidae, and for Z and W homologs of caenophidian species from Acrochordidae, Viperidae, Elapidae, and Colubridae. Female-specific sequences for the two genes were not found in the henophidian (boid and pythonid) species examined. Phylogenetic trees constructed using each gene showed that the Z and W homologs of the caenophidian species cluster separately. The repetitive sequence isolated from the W chromosome heterochromatin of the colubrid Elaphe quadrivirgata and a microsatellite motif (AGAT)8 were strongly hybridized with W chromosomes of the viperid and colubrid species examined.ConclusionOur phylogenetic analyses suggest that the cessation of recombination between the Z and W homologs of CTNNB1 and WAC predated the diversification of the caenophidian families. As the repetitive sequences on the W chromosomes were shared among viperid and colubrid species, heterochromatinization of the proto-W chromosome appears to have occurred before the splitting of these two groups. These results collectively suggest that differentiation of the proto-Z and proto-W chromosomes extended to wide regions on the sex chromosomes in the common ancestor of caenophidian families during a relatively short period.

Dataset Information

Patterns of psychopathology and cognition in sex chromosome aneuploidy.

Background

Methods

Results

Conclusions

Publications

Patterns of psychopathology and cognition in sex chromosome aneuploidy.

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