Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome.

BACKGROUND: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome. METHOD: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes. RESULTS: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network. CONCLUSIONS: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders.

Sex-specific associations between subcortical morphometry in childhood and adult alcohol consumption: A 17-year follow-up study.

Men and women tend to differ in the age of first alcohol consumption, transition into disordered drinking, and the prevalence of alcohol use disorder. Here, we use a unique longitudinal dataset to test for potentially predispositonal sex-biases in brain organization prior to initial alcohol exposure. Our study combines measures of subcortical morphometry gathered in alcohol naive individuals during childhood (mean age: 9.43 years, SD = 2.06) with self-report measures of alcohol use in the same individuals an average of 17 years later (N = 81, 46 males, 35 females). We observe that pediatric amygdala and hippocampus volume both show sex-biased relationships with adult drinking. Specifically, females show a stronger association between subcortical volumetric reductions in childhood and peak drinking in adulthood as compared to males. Detailed analysis of subcortical shape localizes these effects to the rostro-medial hippocampus and basolateral amygdala subnuclei. In contrast, we did not observe sex-specific associations between striatal anatomy and peak alcohol consumption. These results are consistent with a model in which organization of the amygdala and hippocampus in childhood is more relevant for subsequent patterns of peak alcohol use in females as compared to males. Differential neuroanatomical precursors of alcohol use in males and females could provide a potential developmental basis for well recognized sex-differences in alcohol use behaviors.. Thus, our findings not only indicate that brain correlates of human alcohol consumption are manifest long before alcohol initiation, but that some of these correlates are not equivalent between males and females.

Sex Chromosome Dosage Effects on White Matter Structure in the Human Brain.

Sex chromosome aneuploidies, a group of neurogenetic conditions characterized by aberrant sex chromosome dosage (SCD), are associated with increased risks for psychopathology as well as alterations in gray matter structure. However, we still lack a comprehensive understanding of potential SCD-associated changes in white matter structure, or knowledge of how these changes might relate to known alterations in gray matter anatomy. Thus, here, we use voxel-based morphometry on structural neuroimaging data to provide the first comprehensive maps of regional white matter volume (WMV) changes across individuals with varying SCD (n = 306). We show that mounting X- and Y-chromosome dosage are both associated with widespread WMV decreases, including in cortical, subcortical, and cerebellar tracts, as well as WMV increases in the genu of the corpus callosum and posterior thalamic radiation. We also correlate X- and Y-chromosome-linked WMV changes in certain regions to measures of internalizing and externalizing psychopathology. Finally, we demonstrate that SCD-driven WMV changes show a coordinated coupling with SCD-driven gray matter volume changes. These findings represent the most complete maps of X- and Y-chromosome effects on human white matter to date, and show how such changes connect to psychopathological symptoms and gray matter anatomy.

Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY).

Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.

Morphological integration of the human brain across adolescence and adulthood.

Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.

Author Correction: Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans.

Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice-a major model organism for studying neurobiological sex differences-have established: 1) highly consistent sex biases in regional gray matter volume (GMV) involving the cortex and classical subcortical foci, 2) a preponderance of regional GMV sex differences in brain circuits for social and reproductive behavior, and 3) a spatial coupling between regional GMV sex biases and brain expression of sex chromosome genes in adulthood. Here, we directly test translatability of rodent findings to humans. First, using two independent structural-neuroimaging datasets (n > 2,000), we find that the spatial map of sex-biased GMV in humans is highly reproducible (r > 0.8 within and across cohorts). Relative GMV is female biased in prefrontal and superior parietal cortices, and male biased in ventral occipitotemporal, and distributed subcortical regions. Second, through systematic comparison with functional neuroimaging meta-analyses, we establish a statistically significant concentration of human GMV sex differences within brain regions that subserve face processing. Finally, by imaging-transcriptomic analyses, we show that GMV sex differences in human adulthood are specifically and significantly coupled to regional expression of sex-chromosome (vs. autosomal) genes and enriched for distinct cell-type signatures. These findings establish conserved aspects of sex-biased brain development in humans and mice, and shed light on the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.

Transcriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.

Sex chromosome aneuploidy alters the relationship between neuroanatomy and cognition.

Sex chromosome aneuploidy (SCA) increases the risk for cognitive deficits, and confers changes in regional cortical thickness (CT) and surface area (SA). Neuroanatomical correlates of inter-individual variation in cognitive ability have been described in health, but are not well-characterized in SCA. Here, we modeled relationships between general cognitive ability (estimated using full-scale IQ [FSIQ] from Wechsler scales) and regional estimates of SA and CT (from structural MRI scans) in both aneuploid (28 XXX, 55 XXY, 22 XYY, 19 XXYY) and typically-developing euploid (79 XX, 85 XY) individuals. Results indicated widespread decoupling of normative anatomical-cognitive relationships in SCA: we found five regions where SCA significantly altered SA-FSIQ relationships, and five regions where SCA significantly altered CT-FSIQ relationships. The majority of areas were characterized by the presence of positive anatomy-IQ relationships in health, but no or slightly negative anatomy-IQ relationships in SCA. Disrupted anatomical-cognitive relationships generalized from the full cohort to karyotypically defined subcohorts (i.e., XX-XXX; XY-XYY; XY-XXY), demonstrating continuity across multiple supernumerary SCA conditions. As the first direct evidence of altered regional neuroanatomical-cognitive relationships in supernumerary SCA, our findings shed light on potential genetic and structural correlates of the cognitive phenotype in SCA, and may have implications for other neurogenetic disorders.

Sex-biased trajectories of amygdalo-hippocampal morphology change over human development.

The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes - low vs. high areal expansion, and early vs. late growth deceleration. These results (i) bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females, and (ii) uncover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence.

Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance.

Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.

Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology.

Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with human structural brain development is not yet well characterized. Here, we analyzed 1243 longitudinally acquired structural MRI scans from 623 youth (299 female/324 male) to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were stable between ages 5 and 25. Surface-based shape analysis revealed that higher SES is associated with areal expansion of lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and ventrolateral thalamic, and medial amygdalo-hippocampal subregions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Although SES is clearly a complex construct that likely relates to development through diverse, nondeterministic processes, our findings elucidate potential neuroanatomical mediators of the association between SES and cognitive outcomes.SIGNIFICANCE STATEMENT Childhood socioeconomic status (SES) has been associated with developmental disparities in mental health, cognitive ability, and academic achievement, but efforts to understand underlying SES-brain relationships are ongoing. Here, we leverage a unique developmental neuroimaging dataset to longitudinally map the associations between SES and regional brain anatomy at high spatiotemporal resolution. We find widespread associations between SES and global cortical and subcortical volumes and surface area and localize these correlations to a distributed set of cortical, thalamic, and amygdalo-hippocampal subregions. Anatomical variation within a subset of these regions partially mediates the positive relationship between SES and IQ. Our findings help to localize cortical and subcortical systems that represent candidate biological substrates for the known relationships between SES and cognition.

Phonemic and Semantic Verbal Fluency in Sex Chromosome Aneuploidy: Contrasting the Effects of Supernumerary X versus Y Chromosomes on Performance.

OBJECTIVES: Past research suggests that youth with sex chromosome aneuploidies (SCAs) present with verbal fluency deficits. However, most studies have focused on sex chromosome trisomies. Far less is known about sex chromosome tetrasomies and pentasomies. Thus, the current research sought to characterize verbal fluency performance among youth with sex chromosome trisomies, tetrasomies, and pentasomies by contrasting how performance varies as a function of extra X number and X versus Y status. METHODS: Participants included 79 youth with SCAs and 42 typically developing controls matched on age, maternal education, and racial/ethnic background. Participants completed the phonemic and semantic conditions of a verbal fluency task and an abbreviated intelligence test. RESULTS: Both supernumerary X and Y chromosomes were associated with verbal fluency deficits relative to controls. These impairments increased as a function of the number of extra X chromosomes, and the pattern of impairments on phonemic and semantic fluency differed for those with a supernumerary X versus Y chromosome. Whereas one supernumerary Y chromosome was associated with similar performance across fluency conditions, one supernumerary X chromosome was associated with relatively stronger semantic than phonemic fluency skills. CONCLUSIONS: Verbal fluency skills in youth with supernumerary X and Y chromosomes are impaired relative to controls. However, the degree of impairment varies across groups and task condition. Further research into the cognitive underpinnings of verbal fluency in youth with SCAs may provide insights into their verbal fluency deficits and help guide future treatments. (JINS, 2018, 24, 917-927).

Normative brain size variation and brain shape diversity in humans.

Brain size variation over primate evolution and human development is associated with shifts in the proportions of different brain regions. Individual brain size can vary almost twofold among typically developing humans, but the consequences of this for brain organization remain poorly understood. Using in vivo neuroimaging data from more than 3000 individuals, we find that larger human brains show greater areal expansion in distributed frontoparietal cortical networks and related subcortical regions than in limbic, sensory, and motor systems. This areal redistribution recapitulates cortical remodeling across evolution, manifests by early childhood in humans, and is linked to multiple markers of heightened metabolic cost and neuronal connectivity. Thus, human brain shape is systematically coupled to naturally occurring variations in brain size through a scaling map that integrates spatiotemporally diverse aspects of neurobiology.

Sex-chromosome dosage effects on gene expression in humans.

A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation.

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures.

Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.

Allometric Analysis Detects Brain Size-Independent Effects of Sex and Sex Chromosome Complement on Human Cerebellar Organization.

The cerebellum is a large hindbrain structure that is increasingly recognized for its contribution to diverse domains of cognitive and affective processing in human health and disease. Although several of these domains are sex biased, our fundamental understanding of cerebellar sex differences-including their spatial distribution, potential biological determinants, and independence from brain volume variation-lags far behind that for the cerebrum. Here, we harness automated neuroimaging methods for cerebellar morphometrics in 417 individuals to (1) localize normative male-female differences in raw cerebellar volume, (2) compare these to sex chromosome effects estimated across five rare sex (X/Y) chromosome aneuploidy (SCA) syndromes, and (3) clarify brain size-independent effects of sex and SCA on cerebellar anatomy using a generalizable allometric approach that considers scaling relationships between regional cerebellar volume and brain volume in health. The integration of these approaches shows that (1) sex and SCA effects on raw cerebellar volume are large and distributed, but regionally heterogeneous, (2) human cerebellar volume scales with brain volume in a highly nonlinear and regionally heterogeneous fashion that departs from documented patterns of cerebellar scaling in phylogeny, and (3) cerebellar organization is modified in a brain size-independent manner by sex (relative expansion of total cerebellum, flocculus, and Crus II-lobule VIIIB volumes in males) and SCA (contraction of total cerebellar, lobule IV, and Crus I volumes with additional X- or Y-chromosomes; X-specific contraction of Crus II-lobule VIIIB). Our methods and results clarify the shifts in human cerebellar organization that accompany interwoven variations in sex, sex chromosome complement, and brain size.SIGNIFICANCE STATEMENT Cerebellar systems are implicated in diverse domains of sex-biased behavior and pathology, but we lack a basic understanding of how sex differences in the human cerebellum are distributed and determined. We leverage a rare neuroimaging dataset to deconvolve the interwoven effects of sex, sex chromosome complement, and brain size on human cerebellar organization. We reveal topographically variegated scaling relationships between regional cerebellar volume and brain size in humans, which (1) are distinct from those observed in phylogeny, (2) invalidate a traditional neuroimaging method for brain volume correction, and (3) allow more valid and accurate resolution of which cerebellar subcomponents are sensitive to sex and sex chromosome complement. These findings advance understanding of cerebellar organization in health and sex chromosome aneuploidy.

Influences of Brain Size, Sex, and Sex Chromosome Complement on the Architecture of Human Cortical Folding.

Gyrification is a fundamental property of the human cortex that is increasingly studied by basic and clinical neuroscience. However, it remains unclear if and how the global architecture of cortical folding varies with 3 interwoven sources of anatomical variation: brain size, sex, and sex chromosome dosage (SCD). Here, for 375 individuals spanning 7 karyotype groups (XX, XY, XXX, XYY, XXY, XXYY, XXXXY), we use structural neuroimaging to measure a global sulcation index (SI, total sulcal/cortical hull area) and both determinants of sulcal area: total sulcal length and mean sulcal depth. We detail large and patterned effects of sex and SCD across all folding metrics, but show that these effects are in fact largely consistent with the normative scaling of cortical folding in health: larger human brains have disproportionately high SI due to a relative expansion of sulcal area versus hull area, which arises because disproportionate sulcal lengthening overcomes a lack of proportionate sulcal deepening. Accounting for these normative allometries reveals 1) brain size-independent sulcal lengthening in males versus females, and 2) insensitivity of overall folding architecture to SCD. Our methodology and findings provide a novel context for future studies of human cortical folding in health and disease.

Globally Divergent but Locally Convergent X- and Y-Chromosome Influences on Cortical Development.

Owing to their unique evolutionary history, modern mammalian X- and Y-chromosomes have highly divergent gene contents counterbalanced by regulatory features, which preferentially restrict expression of X- and Y-specific genes. These 2 characteristics make opposing predictions regarding the expected dissimilarity of X- vs. Y-chromosome influences on biological structure and function. Here, we quantify this dissimilarity using in vivo neuroimaging within a rare cohort of humans with diverse sex chromosome aneuploidies (SCAs). We show that X- and Y-chromosomes have opposing effects on overall brain size but exert highly convergent influences on local brain anatomy, which manifest across biologically distinct dimensions of the cerebral cortex. Large-scale online meta-analysis of functional neuroimaging data indicates that convergent sex chromosome dosage effects preferentially impact centers for social perception, communication, and decision-making. Thus, despite an almost complete lack of sequence homology, and opposing effects on overall brain size, X- and Y-chromosomes exert congruent effects on the proportional size of cortical systems involved in adaptive social functioning. These convergent X-Y effects (i) track the dosage of those few genes that are still shared by X- and Y-chromosomes, and (ii) may provide a biological substrate for the link between SCA and increased rates of psychopathology.

Everyday executive functions in Down syndrome from early childhood to young adulthood: evidence for both unique and shared characteristics compared to youth with sex chromosome trisomy (XXX and XXY).

Executive functions (EF) are thought to be impaired in Down syndrome (DS) and sex chromosome trisomy (Klinefelter and Trisomy X syndromes; +1X). However, the syndromic specificity and developmental trajectories associated with EF difficulties in these groups are poorly understood. The current investigation (a) compared everyday EF difficulties in youth with DS, +1X, and typical development (TD); and (b) examined relations between age and EF difficulties in these two groups and a TD control group cross-sectionally. Study 1 investigated the syndromic specificity of EF profiles on the Behavior Rating Inventory of Executive Function (BRIEF) in DS (n = 30), +1X (n = 30), and a TD group (n = 30), ages 5-18 years. Study 2 examined age effects on EF in the same cross-sectional sample of participants included in Study 1. Study 3 sought to replicate Study 2's findings for DS by examining age-EF relations in a large independent sample of youth with DS (n = 85) and TD (n = 43), ages 4-24 years. Study 1 found evidence for both unique and shared EF impairments for the DS and +1X groups. Most notably, youth with +1X had relatively uniform EF impairments on the BRIEF scales, while the DS group showed an uneven BRIEF profile with relative strengths and weaknesses. Studies 2 and 3 provided support for fairly similar age-EF relations in the DS and TD groups. In contrast, for the +1X group, findings were mixed; 6 BRIEF scales showed similar age-EF relations to the TD group and 2 showed greater EF difficulties at older ages for +1X. These findings will be discussed within the context of efforts to identify syndrome specific cognitive-behavioral profiles for youth with different genetic syndromes in order to inform basic science investigations into the etiology of EF difficulties in these groups and to develop treatment approaches that are tailored to the needs of these groups.