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Cited by 249Sex and Gender in HealthcareSexual Differentiation and DisordersAutism Spectrum Disorder Research

Sex and gender in neurodevelopmental conditions

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Bölte, Sven, Neufeld, Janina, Marschik, Peter B., Williams, Zachary J., Gallagher, Louise, Lai, Meng-Chuan·2023·Nature Reviews Neurology
DOI 10.1038/s41582-023-00774-6PMC PMC10154737
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Abstract

Health-related conditions often differ qualitatively or quantitatively between individuals of different birth-assigned sexes and gender identities, and/or with different gendered experiences, requiring tailored care. Studying the moderating and mediating effects of sex-related and gender-related factors on impairment, disability, wellbeing and health is of paramount importance especially for neurodivergent individuals, who are diagnosed with neurodevelopmental conditions with uneven sex/gender distributions. Researchers have become aware of the myriad influences that sex-related and gender-related variables have on the manifestations of neurodevelopmental conditions, and contemporary work has begun to investigate the mechanisms through which these effects are mediated. Here we describe topical concepts of sex and gender science, summarize current knowledge, and discuss research and clinical challenges related to autism, attention-deficit/hyperactivity disorder and other neurodevelopmental conditions. We consider sex and gender in the context of epidemiology, behavioural phenotypes, neurobiology, genetics, endocrinology and neighbouring disciplines. The available evidence supports the view that sex and gender are important contributors to the biological and behavioural variability in neurodevelopmental conditions. Methodological caveats such as frequent conflation of sex and gender constructs, inappropriate measurement of these constructs and under-representation of specific demographic groups (for example, female and gender minority individuals and people with intellectual disabilities) limit the translational potential of research so far. Future research and clinical implementation should integrate sex and gender into next-generation diagnostics, mechanistic investigations and support practices.

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  • Interpretationreasoning

    Observed differences among individuals of different sexes or gender identities suggest moderating and sometimes mediating effects of sex/gender attributes on typical and atypical development, including neurodevelopmental conditions.

    “Observed differences among individuals of different sexes or gender identities suggest moderating (and in specific cases, mediating) effects of sex and/or gender attributes on typical and atypical development, including neurodevelopmental conditions (Box 2; Fig. 1).”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Behavioural expressions of neurodevelopmental conditions are modulated by sex and gender in nuanced but clinically important ways.

    “Moreover, behavioural expressions of neurodevelopmental conditions are modulated by sex and gender in nuanced but clinically important ways.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Sex/gender differences range from dimorphic to small differences on a continuum.

    “Depending on the outcome of interest and the specific sex-related or gender-related variable, such differences vary from dimorphic (that is, existing in two forms) to small differences on a continuum (that is, distributions substantially overlap despite mean differences)4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Hines, M. Neuroscience and sex/gender: looking back and forward. J. Neurosci. 40, 37–43 (2020). source

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  • Premisecitation

    Gender diversity has been associated with some neurodevelopmental conditions.

    “Gender diversity has also been associated with some neurodevelopmental conditions16,17 (Box 4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation

    Gender-related attributes can influence biological outcomes thought primarily driven by sex-related attributes.

    “Notably, gender-related attributes can influence biological outcomes that are thought to be primarily driven by sex-related attributes (for example, brain biology, hormonal status and related behaviours)57,58.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • Classified as probably not a substantial claim. 11
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    Premisecitation

    Sex and gender are distinct but inter-correlated multi-component constructs, shaped by biological and sociological mechanisms.

    “Sex and gender are both multi-component umbrella constructs (Box 1); they are distinct but inter-correlated because of interplaying biological and sociological mechanisms52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Many sex-related attributes are treated as dichotomous, but actual distributions can be multi-categorical or continuous.

    “Owing to this conceptual origin, many sex-related attributes are treated as dichotomous (that is, female versus male), but the actual distributions of specific sex-related variables can in some cases be multi-categorical (for example, sex chromosome configurations) or continuous (for example, serum testosterone levels)54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Sex-related attributes are biological and include chromosomal, genetic, gonadal, hormonal, genital and other anatomical and physiological components.

    “Sex-related constructs are biological attributes that were initially conceptualized on the basis of the reproduction of organisms and include chromosomal, genetic, gonadal, hormonal, genital and other anatomical and physiological components53.”
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    Premisecitation

    Most gender-related variables are multi-categorical or continuous, despite ideological binary views.

    “Ideologies that maintain dominating power structures often closely associate gender with sex and impose a binary view of gender, although empirical data show most gender-related variables to be either multi-categorical (for example, gender identities) or continuous (for example, masculinity and femininity)54–56.”
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    • cites [54] Cost, K. T. et al. Checking assumptions: advancing the analysis of sex and gender in human health and psychological sciences. Preprint at OSF Preprints https://doi.org/10.31219/osf.io/c29kg (2022). source

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    Premisecitation

    Level of intellectual functioning modulates the sex/gender ratio in prevalence of some neurodevelopmental conditions; in autism, more balanced ratios are usually found in profound autism and in autistic individuals with co-occurring intellectual disabilities.

    “Level of intellectual functioning modulates the sex/gender ratio in the prevalence of some neurodevelopmental conditions; for example, in autism, more balanced ratios are usually found in individuals with so-called profound autism73 and in autistic individuals with co-occurring intellectual disabilities more generally14,61.”
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    Premisecitation

    The sex/gender bias in prevalence is more pronounced in childhood than adulthood in autism, tic disorders and ADHD, and varies by subtypes.

    “This sex/gender bias has been found to be more pronounced in childhood than in adulthood in autism, tic disorders and ADHD14,19,69–71, and varies for different subtypes of these conditions14,72.”
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    • cites [14] Posserud, M. B., Skretting Solberg, B., Engeland, A., Haavik, J. & Klungsoyr, K. Male to female ratios in autism spectrum disorders by age, intellectual disability and attention-deficit/hyperactivity disorder. Acta Psychiatr. Scand. 144, 635–646 (2021). source

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    Neurodevelopmental conditions are highly heritable but have multifactorial origins involving biology-environment interplay.

    “Neurodevelopmental conditions are highly heritable31,32 but have multifactorial origins alongside biology–environment interplay33–35.”
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    A sex/gender bias towards higher prevalence in males than females is observed across all neurodevelopmental conditions and ranges from 1.2:1 to 4:1.

    “A sex/gender bias towards higher prevalence in males than in females is observed across all neurodevelopmental conditions and ranges from 1.2:1 to 4:1 (Table 1).”
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    • cites Table 1

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    Interpretationcitation

    Despite widespread clinician opinion that co-occurrence profiles differ between sexes/genders, the evidence is inconsistent.

    “Despite the widespread opinion amongst clinicians that the co-occurrence profiles differ between sexes/genders80,81 — with males more likely to show externalizing problems such as oppositional defiant disorder and conduct disorder, and females more likely to show internalizing problems such as anxiety and mood disorders — the evidence is inconsistent.”
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    Autistic males have higher mortality risk from circulatory and nervous system diseases, cancer, and external causes; autistic females have higher risk from similar causes plus endocrine diseases and congenital malformations compared with sex-matched non-autistic counterparts.

    “For example, autistic males have a higher mortality risk from diseases of the circulatory and nervous systems and cancer, and from external causes, and autistic females have a higher risk from similar causes but also from endocrine diseases and congenital malformations compared with sex-matched non-autistic counterparts85,87–89.”
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    Population-based studies show higher rates of suicide in autistic females than autistic males, particularly among individuals in the average IQ range with co-occurring ADHD.

    “Alternatively, population-based studies have shown higher rates of suicide in autistic females than in autistic males85,86, and this finding is particularly pronounced among individuals who are in the average IQ range and have co-occurring ADHD87.”
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    Premisecitation

    Autistic females are more likely to have epilepsy, endocrine-reproductive problems, depressive disorders, and disordered eating and sleep, whereas autistic males are more likely to exhibit hyperactivity in childhood.

    “In terms of health conditions, autistic females are more likely to have epilepsy and endocrine–reproductive problems79,125, depressive disorders78, and disordered eating and sleep126–128, whereas autistic males are more likely to exhibit hyperactivity in childhood124.”
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    Large-scale studies in the last 10 years indicate that cognitive and language abilities vary substantially across sexes and genders in the autistic population, with the most consistent difference being slightly lower restricted and repetitive behaviour scores in females than males.

    “Large-scale studies published in the last 10 years indicate that cognitive and language abilities vary substantially across all sexes and genders in the autistic population, with the most consistent difference being slightly lower restricted and repetitive behaviour scores in females than in males94,104,105.”
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    Interpretationcitation

    Autistic females tend to show better social communication skills than autistic males in nuanced ways, so autistic features in females might not be sufficiently captured by commonly used instruments.

    “For instance, autistic females tend to show better social communication skills than autistic males in nuanced ways, which means that autistic features in females might not be sufficiently captured by commonly used instruments107,108.”
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    Moderating effects of sex/gender on cognitive features associated with autism are mostly observed in executive function and visuospatial domains; autistic males are more likely to have challenges with cognitive flexibility and autobiographical memory, whereas autistic females are more likely to have challenges with response inhibition and visuospatial processing.

    “Moderating effects of sex/gender on cognitive features associated with autism are mostly observed in executive function and visuospatial domains122,123: evidence suggests that autistic males are more likely to have challenges with cognitive flexibility and autobiographical memory, whereas autistic females are more likely to have challenges with response inhibition and visuospatial processing124.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    On average, autistic males and females have similar levels of insistence on sameness; autistic males are more likely to show repetitive motor behaviours and speech and circumscribed interests, whereas autistic females are more likely to experience compulsions and/or self-injurious behaviours.

    “On average, autistic males and females have similar levels of insistence on sameness; autistic males are more likely to show repetitive motor behaviours and speech, and circumscribed interests, whereas autistic females are more likely to experience compulsions and/or self-injurious behaviours115–119.”
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    Premisecitation

    In a Danish registry study, compared with males diagnosed with ADHD, females diagnosed with ADHD had greater rates of co-occurring autism, intellectual disabilities, oppositional defiant disorder, conduct disorder, personality disorders, schizophrenia, substance use disorders and suicidal behaviour.

    “In a Danish population-based registry study, compared with male individuals diagnosed with ADHD, female individuals diagnosed with ADHD had greater rates of co-occurring autism, intellectual disabilities, oppositional defiant disorder and conduct disorder, personality disorders, schizophrenia, substance use disorders and suicidal behaviour82.”
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    • cites [82] Ottosen, C. et al. Sex differences in comorbidity patterns of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 58, 412–422 (2019). source

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    Premisecitation

    In children diagnosed with ADHD, males are more likely to express hyperactivity and females are more likely to show inattention as the predominant presentation; similar patterns have been observed in adults.

    “In children diagnosed with ADHD, males are more likely to express hyperactivity than females, and females are more likely to show inattention as the predominant presentation129,130; similar patterns have also been observed in adults131.”
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    Premisecitation

    Some studies indicate that males diagnosed with ADHD are more likely to show antisocial behaviours and receive oppositional defiant disorder or conduct disorder diagnoses, whereas females are more likely to experience internalizing and emotion regulation problems.

    “Some studies indicate that males diagnosed with ADHD are more likely to show antisocial behaviours and to receive oppositional defiant disorder or conduct disorder diagnoses, whereas females are more likely to experience internalizing and emotion regulation problems106,130.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    • cites [130] Rucklidge, J. J. Gender differences in attention-deficit/hyperactivity disorder. Psychiatr. Clin. North. Am. 33, 357–373 (2010). source

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    Premisecitation

    In adults, registry-based studies indicate that ADHD is more strongly associated with anxiety, depression, bipolar disorder and personality disorders in females than males, and more strongly associated with schizophrenia, substance use disorders and hypertension in males than females.

    “In adults specifically, the results of registry-based studies indicate that ADHD is more strongly associated with anxiety, depression, bipolar disorder and personality disorders in females than in males, and more strongly associated with schizophrenia, substance use disorders and hypertension in males than in females137,138.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [137] Solberg, B. S. et al. Gender differences in psychiatric comorbidity: a population-based study of 40 000 adults with attention deficit hyperactivity disorder. Acta Psychiatr. Scand. 137, 176–186 (2018). source

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    In a longitudinal population study of primary school children aged 4-6, the association between speech-language dysfunctions and medical diagnoses was higher in males than females, and females diagnosed with language disorders were more likely to have morphosyntactic problems than males.

    “In a longitudinal population study of primary school children aged 4–6 years, the association between speech–language dysfunctions and medical diagnoses was higher in males than females, and females diagnosed with language disorders were more likely to have morphosyntactic problems than males143.”
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    • cites [143] Norbury, C. F. et al. The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. J. Child Psychol. Psychiatry 57, 1247–1257 (2016). source

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    Reduced caudate volume in male adults with ADHD compared with neurotypical male adults correlates with hyperactive-impulsive symptoms, but no such effect is observed in female adults.

    “Reduced caudate volume in male adults diagnosed with ADHD compared with neurotypical male adults correlated with hyperactive–impulsive symptoms, whereas no such effect was observed in female adults203.”
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    • cites [203] Onnink, A. M. et al. Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression. Eur. Neuropsychopharmacol. 24, 397–409 (2014). source

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    Premisecitation

    The existence of sex/gender differences in language is controversial, with evidence over the last 10 years indicating that these effects are smaller than previously assumed.

    “However, the existence of sex/gender differences in language is controversial, with evidence published over the last 10 years indicating that these effects are smaller than previously assumed142.”
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    • cites [142] Etchell, A. et al. A systematic literature review of sex differences in childhood language and brain development. Neuropsychologia 114, 19–31 (2018). source

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    Interpretationcitation

    Overall, sex/gender differences in language disorders appear subtle but influence the timing and rates of detection and service access.

    “Overall, there seem to be sex/gender differences in language disorders, which currently appear subtle, but influence the timing and rates of detection and service access.”
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    • cites [143] Norbury, C. F. et al. The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. J. Child Psychol. Psychiatry 57, 1247–1257 (2016). source

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    Premisecitation

    Regarding mathematical skills, findings are mixed, with a tendency for more female than male children to have challenges in this area.

    “Regarding mathematical skills, findings are mixed, with a tendency for more female than male children to have challenges in this area144–146.”
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    • cites [144] Landerl, K. & Moll, K. Comorbidity of learning disorders: prevalence and familial transmission. J. Child Psychol. Psychiatry 51, 287–294 (2010). source

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    • cites [145] Moll, K., Kunze, S., Neuhoff, N., Bruder, J. & Schulte-Korne, G. Specific learning disorder: prevalence and gender differences. PLoS ONE 9, e103537 (2014).

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    • cites [146] Arnett, A. B. et al. Explaining the sex difference in dyslexia. J. Child Psychol. Psychiatry 58, 719–727 (2017). source

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    Premisecitation

    In children, reduced total brain volume is associated with both ADHD and higher polygenic scores for ADHD, and both effects are stronger in males than females.

    “In children, reduced total brain volume has been associated with both ADHD and higher polygenic scores for ADHD, with both these effects stronger in males than in females202.”
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    • cites [202] Mooney, M. A. et al. Smaller total brain volume but not subcortical structure volume related to common genetic risk for ADHD. Psychol. Med. 51, 1279–1288 (2021). source

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    Premisecitation

    In that study, screening for language disorders identified more males than females, and females were often older than males when referred to clinical services.

    “Importantly, in this study, screening for language disorders identified more males than females; indeed, females are often older than males when they are referred to clinical services143.”
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    • cites [143] Norbury, C. F. et al. The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. J. Child Psychol. Psychiatry 57, 1247–1257 (2016). source

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    Premisecitation

    Functional connectivity between striatal and prefrontal regions correlates with increased delay discounting of monetary rewards, a proxy for altered reward functioning and impulsivity, which was elevated only in ADHD females.

    “Functional connectivity between these regions also correlated with increased delay discounting of monetary rewards, a proxy for altered reward functioning and impulsivity, that was elevated in ADHD females only.”
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    • cites [207] Rosch, K. S., Mostofsky, S. H. & Nebel, M. B. ADHD-related sex differences in fronto-subcortical intrinsic functional connectivity and associations with delay discounting. J. Neurodev. Disord. 10, 34 (2018). source

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    Premisecitation

    A study of lateralization found more leftward lateralization in males with ADHD and more rightward lateralization in females with ADHD, in addition to sex/gender-independent ADHD effects.

    “A study that explored lateralization found, in addition to sex/gender-independent effects of ADHD, more leftward lateralization in male individuals diagnosed with ADHD and more rightward lateralization in female individuals diagnosed with ADHD208.”
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    • cites [208] Zou, H. & Yang, J. Exploring the brain lateralization in ADHD based on variability of resting-state fMRI signal. J. Atten. Disord. 25, 258–264 (2021). source

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    Premisecitation

    A study in school-aged children found sex/gender-by-diagnosis interaction effects on white matter microstructure measures, which also correlated with inhibitory control performance.

    “A study in school-aged children identified sex/gender-by-diagnosis interaction effects on measures of white matter microstructure, which also correlated with inhibitory control performance205.”
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    • cites [205] Jacobson, L. A. et al. Sex-based dissociation of white matter microstructure in children with attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 54, 938–946 (2015). source

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    Interpretationcitation

    These findings might be potential evidence for sex/gender differences in brain maturation delays linked to ADHD, although the study assessed adults.

    “These findings might be potential evidence for sex/gender differences in brain maturation delays linked to ADHD, although the study assessed adults.”
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    A study of callosal fibre tracts found a sex/gender-by-diagnosis interaction on radial diffusivity in posterior parietal tracts; diffusivity was altered only in females with ADHD and correlated with attention control in both sexes/genders.

    “Another study, which assessed callosal fibre tracts, found a sex/gender-by-diagnosis interaction effect on radial diffusivity in the posterior parietal tracts; diffusivity was altered only in females diagnosed with ADHD and correlated with attention control in both sexes/genders206.”
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    • cites [206] Lin, Q. et al. Sex differences in microstructural alterations in the corpus callosum tracts in drug-naive children with ADHD. Brain Imaging Behav. 16, 1592–1604 (2022). source

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    Premisecitation

    Compared with neurotypical participants, males with ADHD had fractional anisotropy alterations in primary motor regions, whereas females with ADHD had alterations in medial orbitofrontal regions.

    “More specifically, compared with neurotypical participants, males diagnosed with ADHD had alterations in fractional anisotropy in primary motor regions, whereas ADHD females had alterations in medial orbitofrontal regions.”
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    • cites [205] Jacobson, L. A. et al. Sex-based dissociation of white matter microstructure in children with attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 54, 938–946 (2015). source

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    Premisecitation

    Another study found sex/gender differences in cerebellar choline and glutamate-glutamine concentrations, with lower levels in females, and age-by-sex/gender interactions for choline, creatine and glutamate-glutamine concentrations in the pregenual anterior cingulate cortex in adults with ADHD.

    “Another study found sex/gender differences in cerebellar choline and glutamate–glutamine concentrations with lower levels in females and interaction effects between age and sex/gender for choline, creatine and glutamate–glutamine concentrations in the pregenual anterior cingulate cortex in adults diagnosed with ADHD212.”
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    • cites [212] Endres, D. et al. Neurochemical sex differences in adult ADHD patients: an MRS study. Biol. Sex. Differ. 10, 50 (2019). source

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    Premisecitation

    These changes include reduced whole-brain volume, reduced right hemispheric grey matter and bilateral white matter volume, and an increased left-hemispheric grey matter to white matter ratio compared with neurotypical individuals.

    “These changes include reduced whole-brain volume, reduced right hemispheric grey matter and bilateral white matter volume, and an increased left-hemispheric grey matter to white matter ratio, as compared with neurotypical individuals.”
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    • cites [147] Krafnick, A. J. & Evans, T. M. Neurobiological sex differences in developmental dyslexia. Front. Psychol. 9, 2669 (2019). source

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    Premisecitation

    Compared with neurotypical children, male children with Tourette syndrome have alterations in cortical and callosal thickness and basal ganglia volume; these alterations were not observed in female children with Tourette syndrome.

    “Preliminary findings indicate that, compared with neurotypical children, male children with Tourette syndrome have alterations in cortical and callosal thickness and basal ganglia volume; these alterations were not observed in female children with Tourette syndrome149,216.”
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    • cites [149] Garris, J. & Quigg, M. The female Tourette patient: sex differences in Tourette disorder. Neurosci. Biobehav. Rev. 129, 261–268 (2021). source

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    • cites [216] Pinares-Garcia, P., Stratikopoulos, M., Zagato, A., Loke, H. & Lee, J. Sex: a significant risk factor for neurodevelopmental and neurodegenerative disorders. Brain Sci. 8, 154 (2018). source

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    Interpretationreasoning

    Current evidence suggests that males with Tourette syndrome might have more widespread brain alterations than their neurotypical counterparts than do females with Tourette syndrome, and that typical brain sex/gender differences are reduced in individuals with Tourette syndrome.

    “Overall, current evidence suggests that males with Tourette syndrome might have more widespread brain alterations than their neurotypical counterparts than do females with Tourette syndrome, and that typical brain sex/gender differences are reduced in individuals diagnosed with Tourette syndrome.”
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    Interpretationcitation

    Preliminary evidence suggests structural brain alterations are more anatomically widespread in dyslexic females than in dyslexic males, who have clearer involvement of classic reading network regions.

    “Preliminary evidence suggests that structural brain alterations are more anatomically widespread in dyslexic females than in dyslexic males, who have a clearer involvement of the classic reading network regions147.”
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    • cites [147] Krafnick, A. J. & Evans, T. M. Neurobiological sex differences in developmental dyslexia. Front. Psychol. 9, 2669 (2019). source

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    Premisecitation

    Altered left-right asymmetry of the planum temporale and reductions in left-hemispheric grey matter cortical thickness in several regions have been observed in dyslexic male individuals compared with neurotypical male individuals.

    “In contrast, altered left–right asymmetry of the planum temporale214, and reductions in left-hemispheric grey matter cortical thickness in the middle and superior temporal gyri, orbitofrontal cortex, inferior frontal gyrus, temporoparietal cortex and fusiform gyrus have been observed in dyslexic male individuals compared with neurotypical male individuals147.”
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    • cites [147] Krafnick, A. J. & Evans, T. M. Neurobiological sex differences in developmental dyslexia. Front. Psychol. 9, 2669 (2019). source

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    • cites [214] Ramus, F., Altarelli, I., Jednoróg, K., Zhao, J. & Scotto di Covella, L. in Dyslexia and Neuroscience: The Geschwind-Galaburda Hypothesis 30 Years Later Ch. 7 (eds Galaburda, A. M., Gaab, N., Hoeft, F. & McCardle, P.) 78–86 (Brookes, 2018).

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    Premisecitation

    A 1H-MRS study found higher levels of choline and myoinositol associated with reduced processing speed across dyslexic and neurotypical female children; this association was not observed in male children.

    “One 1H-MRS study assessed neurotransmitter metabolite concentrations in the anterior cingulate cortex and identified higher levels of choline and myoinositol in association with reduced processing speed across dyslexic and neurotypical female children; this association was not observed in male children215.”
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    • cites [215] Horowitz-Kraus, T., Brunst, K. J. & Cecil, K. M. Children with dyslexia and typical readers: sex-based choline differences revealed using proton magnetic resonance spectroscopy acquired within anterior cingulate cortex. Front. Hum. Neurosci. 12, 466 (2018). source

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    Premisecitation

    A study found reduced cortical thickness in prefrontal, orbitofrontal and parietal regions in males with Tourette syndrome compared with females with Tourette syndrome, and a negative correlation between tic severity and post-central and pre-central regions that was significantly stronger in males than females.

    “One study found reduced cortical thickness in prefrontal, orbitofrontal and parietal regions in males with Tourette syndrome compared with females with Tourette syndrome, as well as a negative correlation between tic severity and post-central and pre-central regions that was significantly stronger in males than in females217.”
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    • cites [217] Fahim, C. et al. Somatosensory-motor bodily representation cortical thinning in Tourette: effects of tic severity, age and gender. Cortex 46, 750–760 (2010). source

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    Premisecitation

    The effects of IQ are usually insufficiently captured in neuroimaging studies of sex/gender in neurodevelopmental conditions, with most studies controlling for IQ as a nuisance covariate or excluding participants with intellectual disabilities.

    “Furthermore, the effects of IQ are usually insufficiently captured in neuroimaging studies of sex/gender in neurodevelopmental conditions188,221, with the majority of studies controlling for IQ as a nuisance covariate or simply excluding participants with intellectual disabilities174.”
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    • cites [188] Chien, Y. L. et al. Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD. Mol. Psychiatry 27, 3262–3271 (2022). source

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    • cites [221] Gharehgazlou, A. et al. Cortical gyrification morphology in individuals with ASD and ADHD across the lifespan: a systematic review and meta-analysis. Cereb. Cortex 31, 2653–2669 (2021). source

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    • cites [174] Hammill, C. et al. Quantitative and qualitative sex modulations in the brain anatomy of autism. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 6, 898–909 (2021).

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    Premisecitation

    Genetic propensity for various neurodevelopmental conditions can be associated with sex-differentiated phenotypic heterogeneity; for example, male siblings of females with anxiety disorders have elevated relative likelihoods of ADHD or any neurodevelopmental condition, although this effect could also represent diagnostic sex/gender bias.

    “Genetic propensity for various neurodevelopmental conditions can be associated with sex-differentiated phenotypic heterogeneity; for example, male siblings of females with anxiety disorders have elevated relative likelihoods of ADHD or any neurodevelopmental condition, although this effect could also represent a diagnostic sex/gender bias232.”
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    • cites [232] Martin, J. et al. Investigating gender-specific effects of familial risk for attention-deficit hyperactivity disorder and other neurodevelopmental disorders in the Swedish population. BJPsych Open 6, e65 (2020). source

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    Premisecitation

    In ADHD, mothers diagnosed with ADHD transmit a greater likelihood of ADHD to offspring than fathers, although this has not been found in all studies.

    “Similarly, in the context of ADHD, mothers diagnosed with ADHD transmit a greater likelihood of ADHD to offspring than fathers230, although this has not been found in all studies231.”
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    • cites [230] Solberg, B. S. et al. Sex differences in parent-offspring recurrence of attention-deficit/hyperactivity disorder. J. Child Psychol. Psychiatry 62, 1010–1018 (2021). source

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    • cites [231] Mouridsen, S. E., Rich, B. & Isager, T. The sex ratio of full and half siblings of people diagnosed with ADHD in childhood and adolescence: a Danish nationwide register-based cohort study. J. Atten. Disord. 20, 1017–1022 (2016). source

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    Premisecitation

    During eye-gaze processing, females with FXS show reduced insula and fusiform gyrus activation, whereas males with FXS show increased amygdala and insula activation, compared with neurotypical individuals.

    “During eye-gaze processing, females with FXS show reduced insula and fusiform gyrus activation, whereas males with FXS show increased amygdala and insula activation, as compared with neurotypical individuals164.”
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    • cites [164] Hagerman, R. J. et al. Fragile X syndrome. Nat. Rev. Dis. Prim. 3, 17065 (2017). source

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    Premisecitation

    Higher autism prevalence occurs among individuals with a close autistic female relative, and the likelihood of autism increases in later-born offspring siblings of autistic females compared with autistic males (the Carter effect).

    “Higher autism prevalence (compared with that in the general population) occurs among individuals who have a close autistic female relative and the likelihood of autism increases in later-born offspring siblings of autistic females, compared with autistic males (known as the Carter effect)227–229.”
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    • cites [227] Palmer, N. et al. Association of sex with recurrence of autism spectrum disorder among siblings. JAMA Pediatr. 171, 1107–1112 (2017). source

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    • cites [228] Wigdor, E. M. et al. The female protective effect against autism spectrum disorder. Cell Genomics 2, 100134 (2022). source

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    • cites [229] Warrier, V. et al. Genetic correlates of phenotypic heterogeneity in autism. Nat. Genet. 54, 1293–1304 (2022). source

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    Premisecitation

    Polygenic scores for autism are increased in autistic females without intellectual disabilities, in non-autistic mothers and female siblings, and in mothers with broader subdiagnostic autism phenotypes.

    “Polygenic scores for autism, based on the weighted sum of susceptibility alleles present, are increased in autistic females without intellectual disabilities229, in non-autistic mothers and female siblings228, and in mothers with broader subdiagnostic autism phenotypes233.”
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    • cites [229] Warrier, V. et al. Genetic correlates of phenotypic heterogeneity in autism. Nat. Genet. 54, 1293–1304 (2022). source

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    • cites [228] Wigdor, E. M. et al. The female protective effect against autism spectrum disorder. Cell Genomics 2, 100134 (2022). source

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    • cites [233] Nayar, K. et al. Elevated polygenic burden for autism spectrum disorder is associated with the broad autism phenotype in mothers of individuals with autism spectrum disorder. Biol. Psychiatry 89, 476–485 (2021). source

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    Premisecitation

    X-linked neurodevelopmental conditions, FXS and Rett syndrome, are associated with sex-differentiated behavioural and developmental outcomes in human and animal studies, although this is not universal for X-linked genes.

    “X-linked neurodevelopmental conditions, FXS and Rett syndrome, are associated with sex-differentiated behavioural and developmental outcomes in human and animal studies242 although this is not universal for X-linked genes243.”
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    • cites [242] Worsham, W., Dalton, S. & Bilder, D. A. The prenatal hormone milieu in autism spectrum disorder. Front. Psychiatry 12, 655438 (2021). source

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    • cites [243] Martin, H. C. et al. The contribution of X-linked coding variation to severe developmental disorders. Nat. Commun. 12, 627 (2021).

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    Premisecitation

    Autism diagnosis prevalence is almost double in individuals with XYY syndrome (on average 30%) than in individuals with XXY syndrome (18%) and XXX syndrome (15%), although it is still higher in individuals with the latter two syndromes than in the general population.

    “For example, autism diagnosis prevalence is almost double in individuals with XYY syndrome (on average 30%) than in individuals with XXY syndrome (18%) and XXX syndrome (15%), although it is still higher in individuals with the latter two syndromes than in the general population239.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] van Rijn, S. A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47,XYY). Curr. Opin. Psychiatry 32, 79–84 (2019). source

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    Premisecitation

    Chromosomal dosage might influence SCA phenotypes owing to excess or reduced sex chromosome number; for example, a supernumerary Y chromosome is particularly associated with reduced social and attentional functioning.

    “Chromosomal dosage might influence SCA phenotypes owing to excess or reduced sex chromosome number; for example, a supernumerary Y chromosome is particularly associated with reduced social and attentional functioning240.”
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    • cites [240] Rau, S. et al. Patterns of psychopathology and cognition in sex chromosome aneuploidy. J. Neurodev. Disord. 13, 61 (2021). source

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    Premisecitation

    Autistic females are more likely than autistic males to carry a higher burden of de novo rare variants, which is inversely related to polygenic score load.

    “Autistic females are also more likely than autistic males to carry a higher burden of de novo rare variants235,236, which is inversely related to polygenic score load236.”
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    • cites [235] Zhang, Y. et al. Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect. Transl. Psychiatry 10, 4 (2020).

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    • cites [236] Antaki, D. et al. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex. Nat. Genet. 54, 1284–1292 (2022). source

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    Premisecitation

    Studying XCI and escape genes in humans is methodologically challenging and difficult to relate to human brain tissues, although catalogues of XCI across human tissues have helped identify genes contributing to sex-specific differences.

    “Studying XCI and escape genes in humans is methodologically challenging254 and difficult to relate to human brain tissues244, although catalogues of XCI across human tissues have helped identify genes contributing to sex-specific differences255.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [254] Geens, M. et al. Female human pluripotent stem cells rapidly lose X chromosome inactivation marks and progress to a skewed methylation pattern during culture. Mol. Hum. Reprod. 22, 285–298 (2016). source

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    • cites [244] Brand, B. A., Blesson, A. E. & Smith-Hicks, C. L. The impact of X-chromosome inactivation on phenotypic expression of X-linked neurodevelopmental disorders. Brain Sci. 11, 904 (2021). source

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    • cites [255] Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017). source

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    Premisecitation

    Some autosomal genes show sexually differentiated expression in the context of neurodevelopmental conditions; for example, genes involved in the Wnt signalling pathway in ADHD and SHANK1 in autism.

    “Some autosomal genes show sexually differentiated expression in the context of neurodevelopmental conditions; for example, genes involved in the Wnt signalling pathway in ADHD248 and SHANK1 in autism249.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [248] Grunblatt, E. et al. The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: association study and meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 180, 365–376 (2019). source

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    • cites [249] Berkel, S. et al. Sex hormones regulate SHANK expression. Front. Mol. Neurosci. 11, 337 (2018). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 2019 publication describes a method for estimating X-linked gene dosage from genome-wide association study summary statistics, which will aid investigation of X-linked variation in complex traits.

    “A publication from 2019 describes a method for the estimation of X-linked gene dosage from the summary statistics of genome-wide association studies, which will aid in the investigation of X-linked variation in complex traits253.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Sidorenko, J. et al. The effect of X-linked dosage compensation on complex trait variation. Nat. Commun. 10, 3009 (2019). source

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    Premisecitation

    Evidence suggests that XCI skewing can cause phenotypic variability among female family members with FXS, but evidence regarding the role of XCI in the Rett syndrome phenotype is inconclusive.

    “Evidence suggests that XCI skewing can cause phenotypic variability among female family members with FXS, but evidence regarding the role of XCI in the Rett syndrome phenotype is inconclusive244.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Brand, B. A., Blesson, A. E. & Smith-Hicks, C. L. The impact of X-chromosome inactivation on phenotypic expression of X-linked neurodevelopmental disorders. Brain Sci. 11, 904 (2021). source

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    Premisecitation

    Y chromosome genes that could contribute to sex bias in neurodevelopmental conditions include NLGN4Y, an autism candidate gene, and SRY, a brain-expressed gene that stimulates male gonadal development and fetal testosterone production.

    “Y chromosome genes that could contribute to sex bias in neurodevelopmental conditions include NLGN4Y, an autism candidate gene246, and SRY247, a brain-expressed gene that stimulates male gonadal development and fetal testosterone production.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [246] Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27–29 (2003). source

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    • cites [247] Tahira, A. C. et al. Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 180, 390–414 (2019). source

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    Premisecitation

    Studies investigating the female protective effect in autism have used partly overlapping samples, and independent replication is therefore required.

    “Studies investigating the so-called female protective effect in autism have used partly overlapping samples, and independent replication is therefore required225,227–229,236.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [225] Robinson, E. B., Lichtenstein, P., Anckarsater, H., Happe, F. & Ronald, A. Examining and interpreting the female protective effect against autistic behavior. Proc. Natl Acad. Sci. USA 110, 5258–5262 (2013). source

      Not checked in the free run.

    • cites [227] Palmer, N. et al. Association of sex with recurrence of autism spectrum disorder among siblings. JAMA Pediatr. 171, 1107–1112 (2017). source

      Not checked in the free run.

    • cites [228] Wigdor, E. M. et al. The female protective effect against autism spectrum disorder. Cell Genomics 2, 100134 (2022). source

      Not checked in the free run.

    • cites [229] Warrier, V. et al. Genetic correlates of phenotypic heterogeneity in autism. Nat. Genet. 54, 1293–1304 (2022). source

      Not checked in the free run.

    • cites [236] Antaki, D. et al. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex. Nat. Genet. 54, 1284–1292 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Genetic contributions to sex differences in neurodevelopmental conditions are small and polygenic, and large sample sizes are typically required to detect the effects.

    “In summary, genetic contributions to sex differences in neurodevelopmental conditions are small and polygenic, and large sample sizes are typically required to detect the effects252.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252] Martin, J. et al. Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits. Biol. Psychiatry 89, 1127–1137 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Steroid hormones, particularly androgens, might be biological mediators and potential moderators for genetic aetiological factors of demonstrated sex differences in autism prevalence.

    “Steroid hormones, particularly androgens, might be biological mediators (and potential moderators for genetic aetiological factors256) of demonstrated sex differences in autism prevalence.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Terloyeva, D. et al. Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort. Mol. Autism 11, 93 (2020). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sodium valproate is an important teratogen associated with cognitive deficits and autism in humans.

    “Sodium valproate is an important teratogen associated with cognitive deficits and autism in humans33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Bölte, S., Girdler, S. & Marschik, P. B. The contribution of environmental exposure to the etiology of autism spectrum disorder. Cell Mol. Life Sci. 76, 1275–1297 (2019). source

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    Evidence of neuroinflammation has been observed in post-mortem studies in individuals who had neurodevelopmental conditions, and gene expression studies indicate microglial over-activation.

    “Evidence of neuroinflammation has been observed in post-mortem studies in individuals who had neurodevelopmental conditions, and gene expression studies indicate microglial over-activation277,282,283.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [277] Kissel, L. T. & Werling, D. M. Neural transcriptomic analysis of sex differences in autism spectrum disorder: current insights and future directions. Biol. Psychiatry 91, 53–60 (2022). source

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    • cites [282] Lennington, J. B. et al. Transcriptome analysis of the human striatum in Tourette syndrome. Biol. Psychiatry 79, 372–382 (2016). source

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    • cites [283] Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011). source

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    Sex/gender differences in immunological responses are present across the lifespan and contribute to differential susceptibility to infections and autoimmune diseases in the general population.

    “Sex/gender differences in immunological responses are present across the lifespan and contribute to differential susceptibility to infections and autoimmune diseases in the general population278.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [278] Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016). source

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    Premisecitation

    Evidence suggests that maternal obesity results in early maturation of the fetal hypothalamic-pituitary-adrenal axis, which might alter fetal neural programming and promote sex-specific neurodevelopmental outcomes.

    “Evidence suggests that maternal obesity results in early maturation of the fetal hypothalamic–pituitary–adrenal axis, which might alter fetal neural programming and promote sex-specific neurodevelopmental outcomes272,273.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [272] Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 17, 564–579 (2021). source

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    • cites [273] Kim, D. W., Glendining, K. A., Grattan, D. R. & Jasoni, C. L. Maternal obesity leads to increased proliferation and numbers of astrocytes in the developing fetal and neonatal mouse hypothalamus. Int. J. Dev. Neurosci. 53, 18–25 (2016). source

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    Evidence from animal and human studies suggests that endocrine-disrupting compounds such as bisphenol A affect neurodevelopmental outcomes via immune cell functioning, although most human studies are limited by imprecise measures of exposure.

    “Evidence from animal and human studies also suggests that endocrine-disrupting compounds such as bisphenol A affect neurodevelopmental outcomes via immune cell functioning274, although most human studies are limited by imprecise measures of exposure and more rigorous epidemiological studies are warranted275.”
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    • cites [274] Lee, S. C. et al. Solving for X: evidence for sex-specific autism biomarkers across multiple transcriptomic studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 180, 377–389 (2019). source

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    • cites [275] Marí-Bauset, S. et al. Systematic review of prenatal exposure to endocrine disrupting chemicals and autism spectrum disorder in offspring. Autism 26, 6–32 (2022). source

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    Premisecitation

    Obesity is associated with a pro-inflammatory state, suggesting a role for maternal immune activation in the development of neurodevelopmental conditions.

    “In addition to metabolic and neuroendocrine effects, obesity is associated with a pro-inflammatory state, suggesting a role for maternal immune activation in the development of neurodevelopmental conditions272.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [272] Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 17, 564–579 (2021). source

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    Premisecitation

    Maternal prenatal infections increase the likelihood of autism (though potentially not causally), intellectual disabilities and ADHD in offspring, and the presence of specific inflammatory disease states during pregnancy is associated with autism, ADHD and Tourette syndrome.

    “Maternal prenatal infections increase the likelihood of autism (though potentially not causally280), intellectual disabilities and ADHD in offspring, and the presence of specific inflammatory disease states during pregnancy (for example, maternal asthma, diabetes or autoimmune diseases) has been associated with autism, ADHD and Tourette syndrome272,281.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [280] Brynge, M. et al. Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study. Lancet Psychiatry 9, 782–791 (2022). source

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    • cites [272] Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 17, 564–579 (2021). source

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    • cites [281] Solek, C. M., Farooqi, N., Verly, M., Lim, T. K. & Ruthazer, E. S. Maternal immune activation in neurodevelopmental disorders. Dev. Dyn. 247, 588–619 (2018). source

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    Evidence suggests that the gut-brain axis and microbiome can modulate brain development and behaviour, impacting mental health and neurodevelopmental outcomes while also interacting with sex-related attributes.

    “Evidence suggests that the gut–brain axis and microbiome can modulate brain development and behaviour293, impacting mental health and neurodevelopmental outcomes294 while also interacting with sex-related attributes295.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [293] Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). source

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    • cites [294] Holingue, C. et al. Sex differences in the gut-brain axis: implications for mental health. Curr. Psychiatry Rep. 22, 83 (2020). source

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    • cites [295] Jaggar, M., Rea, K., Spichak, S., Dinan, T. G. & Cryan, J. F. You’ve got male: sex and the microbiota-gut-brain axis across the lifespan. Front. Neuroendocrinol. 56, 100815 (2020). source

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  • May combine two claims.

    Interpretationreasoning

    Although solid evidence exists that some immunological mechanisms differ for females and males in the general population, and it is likely that immune processes are altered in neurodevelopmental conditions, the study of sex/gender differences in immune responses and mechanisms in neurodivergent populations is still in its infancy.

    “In short, although solid evidence exists that some immunological mechanisms differ for females and males in the general population, and it is likely that immune processes are altered in neurodevelopmental conditions, the study of sex/gender differences in immune responses and mechanisms in neurodivergent populations is still in its infancy.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Male, but not female, offspring of exposed mice exhibited elevated IL-6 cytokine levels and repetitive-restricted behaviours compared with sex-matched offspring of control mice.

    “For example, male, but not female, offspring of exposed mice exhibited elevated IL-6 cytokine levels and repetitive-restricted behaviours compared with sex-matched offspring of control mice288–290.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [288] Xuan, I. C. & Hampson, D. R. Gender-dependent effects of maternal immune activation on the behavior of mouse offspring. PLoS ONE 9, e104433 (2014).

      Not checked in the free run.

    • cites [289] Custódio, C. S. et al. Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: relevance to autism spectrum disorders. Mol. Neurobiol. 55, 3775–3788 (2018).

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    • cites [290] Turano, A., Lawrence, J. H. & Schwarz, J. M. Activation of neonatal microglia can be influenced by other neural cells. Neurosci. Lett. 657, 32–37 (2017). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the general population, some gastrointestinal disorders are more common in males (for example, diarrhoea) and some are more common in females (for example, functional dyspepsia and irritable bowel syndrome); they are also more often associated with anxiety and depression in females.

    “In the general population, some gastrointestinal disorders are more common in males (for example, diarrhoea) and some are more common in females (for example, functional dyspepsia and irritable bowel syndrome); they are also more often associated with anxiety and depression in females296.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [296] Narayanan, S. P., Anderson, B. & Bharucha, A. E. Sex- and gender-related differences in common functional gastroenterologic disorders. Mayo Clin. Proc. 96, 1071–1089 (2021). source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The mechanisms by which sex-related and gender-related attributes exert their effects on neurodevelopmental outcomes are likely to include a wide range of interacting biological, psychological and sociocultural processes.

    “Notably, the mechanisms by which sex-related and gender-related attributes exert their effects on neurodevelopmental outcomes are likely to include a wide range of interacting biological, psychological and sociocultural processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Although gender terminology is used increasingly in research, most studies have investigated the moderating effect(s) of sex-labels assigned at birth, which only serve as a proxy of the joint effects of sex-related biological factors and gender-related attributes beyond gender identity.

    “Foremost, although gender terminology is used increasingly in research, most studies have investigated the moderating effect(s) of sex-labels assigned at birth, which only serve as a proxy of the joint effects of sex-related biological factors and gender-related attributes beyond gender identity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although research shows that gut-brain axis and microbiome influences on mental health issues and neurodevelopmental conditions might affect females and males differently, exact findings on mechanisms are lacking.

    “To summarize, although research shows that the gut–brain axis and microbiome influences on mental health issues and neurodevelopmental conditions might affect females and males differently, exact findings on mechanisms are lacking.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In animal studies, sex-specific gut microbiota profiles were detected in the BTBR mouse model of autism, and prenatal exposure to elevated levels of microbiome products generated subtle sex differences in social behaviour and activity levels at different points during development.

    “In addition, in animal studies, sex-specific gut microbiota profiles were detected in the BTBR mouse model of autism, and prenatal exposure to elevated levels of microbiome products generated subtle sex differences in social behaviour and activity levels at different points during development291,300.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [291] Coretti, L. et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci. Rep. 7, 45356 (2017). source

      Not checked in the free run.

    • cites [300] Foley, K. A., MacFabe, D. F., Vaz, A., Ossenkopp, K. P. & Kavaliers, M. Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: implications for autism spectrum disorders. Int. J. Dev. Neurosci. 39, 68–78 (2014). source

      Not checked in the free run.

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    Premisecitation

    Associations between neurodevelopmental conditions, particularly autism and ADHD, and gastrointestinal problems are established, but specific microbiome signatures have yet to be identified.

    “Associations between neurodevelopmental conditions, particularly autism and ADHD, and gastrointestinal problems are established but specific microbiome signatures have yet to be identified77,297,298.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Pan, P. Y. & Bölte, S. The association between ADHD and physical health: a co-twin control study. Sci. Rep. 10, 22388 (2020).

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    • cites [297] Isaksson, J., Pettersson, E., Kostrzewa, E., Diaz Heijtz, R. & Bölte, S. Brief report: association between autism spectrum disorder, gastrointestinal problems and perinatal risk factors within sibling pairs. J. Autism Dev. Disord. 47, 2621–2627 (2017). source

      Not checked in the free run.

    • cites [298] Andreo-Martínez, P., Rubio-Aparicio, M., Sánchez-Meca, J., Veas, A. & Martínez-González, A. E. A meta-analysis of gut microbiota in children with autism. J. Autism Dev. Disord. 52, 1374–1387 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    In autism, there is more support for qualitative sex/gender brain differences, with more widespread and qualitatively different network alterations in females compared with males.

    “In autism, there is more support for qualitative sex/gender brain differences, with more widespread and qualitatively different network alterations in females compared with males.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The strength of the evidence varies from established to emerging and is drawn from epidemiological, behavioural, cognitive, neurobiological, genetic, endocrinological and immunological research.

    “The strength of this evidence varies — from established to emerging — and is drawn from epidemiological, behavioural, cognitive, neurobiological, genetic, endocrinological and immunological research.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Research in humans is limited by methodological challenges and an incomplete understanding of the complex interactions between genetic, endocrine, metabolic and immune factors.

    “Research in humans is limited by methodological challenges and an incomplete understanding of the complex interactions between genetic, endocrine, metabolic and immune factors.”
    Quote in the paperSubstantial claim

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    Premisereasoning

    Substantial methodological problems arise from the inappropriate conflation of sex and gender attributes and the systemic under-representation of specific subpopulations.

    “Substantial methodological problems arise from the inappropriate conflation of sex and gender attributes and the systemic under-representation of specific subpopulations.”
    Quote in the paperSubstantial claim

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    Premisereasoning

    Many studies include small numbers of females and gender-minority individuals and therefore frequently lack the statistical power to conduct sex-focused and gender-focused analyses.

    “Further, many studies include small numbers of females and gender-minority individuals and therefore frequently lack the statistical power to conduct sex-focused and gender-focused analyses.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Research has been instrumental in raising clinical awareness of sex and gender nuances, especially in autism and ADHD, and improving the timely and effective identification and support of neurodivergent females.

    “Research has been instrumental in raising clinical awareness of such nuances, especially in autism and ADHD106,133, and improving the timely and effective identification and support of neurodivergent females.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [106] Lai, M. C., Lin, H. Y. & Ameis, S. H. Towards equitable diagnoses for autism and attention-deficit/hyperactivity disorder across sexes and genders. Curr. Opin. Psychiatry 35, 90–100 (2022). source

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    • cites [133] Hinshaw, S. P., Nguyen, P. T., O’Grady, S. M. & Rosenthal, E. A. Annual research review: attention-deficit/hyperactivity disorder in girls and women: underrepresentation, longitudinal processes, and key directions. J. Child Psychol. Psychiatry 63, 484–496 (2022). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    Some widely cited constructs and models require reconsideration and refinement.

    “Third, some widely cited constructs and models require reconsideration and refinement.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Discussions about the validity and conceptual clarity of the so-called female autism phenotype, camouflaging and the female protective effect are ongoing.

    “Discussions about the validity and conceptual clarity of the so-called female (autism) phenotype106,309,310, camouflaging109,311–315 and female protective effect226,316 are ongoing.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [106] Lai, M. C., Lin, H. Y. & Ameis, S. H. Towards equitable diagnoses for autism and attention-deficit/hyperactivity disorder across sexes and genders. Curr. Opin. Psychiatry 35, 90–100 (2022). source

      Not checked in the free run.

    • cites [309] Lai, M. C. & Szatmari, P. Sex and gender impacts on the behavioural presentation and recognition of autism. Curr. Opin. Psychiatry 33, 117–123 (2020). source

      Not checked in the free run.

    • cites [310] Hull, L., Petrides, K. V. & Mandy, W. The female autism phenotype and camouflaging: a narrative review. Rev. J. Autism Dev. Disord. 7, 306–317 (2020). source

      Not checked in the free run.

    • cites [109] Ai, W., Cunningham, W. A. & Lai, M. C. Reconsidering autistic ‘camouflaging’ as transactional impression management. Trends Cogn. Sci. 26, 631–645 (2022). source

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    • cites [311] Fombonne, E. Camouflage and autism. J. Child Psychol. Psychiatry 61, 735–738 (2020). source

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    • cites [312] Cook, J., Hull, L., Crane, L. & Mandy, W. Camouflaging in autism: a systematic review. Clin. Psychol. Rev. 89, 102080 (2021). source

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    • cites [313] Libsack, E. J. et al. A systematic review of passing as non-autistic in autism spectrum disorder. Clin. Child Fam. Psychol. Rev. 24, 783–812 (2021). source

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    • cites [314] Lai, M. C. et al. Commentary: ‘Camouflaging’ in autistic people – reflection on Fombonne (2020). J. Child Psychol. Psychiatry 62, 1037–1041 (2021).

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    • cites [315] Williams, Z. J. Commentary: the construct validity of ‘camouflaging’ in autism: psychometric considerations and recommendations for future research – reflection on Lai et al. (2020). J. Child Psychol. Psychiatry 63, 118–121 (2022). source

      Not checked in the free run.

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    Premisecitation

    Sex/gender ratios, behavioural and biological phenotypes, and co-occurring conditions change over time, and there are cohort effects.

    “Second, sex/gender ratios, behavioural and biological phenotypes, and co-occurring conditions change over time, and there are cohort effects306.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [306] Arvidsson, O., Gillberg, C., Lichtenstein, P. & Lundstrom, S. Secular changes in the symptom level of clinically diagnosed autism. J. Child Psychol. Psychiatry 59, 744–751 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Most research focuses on autism, and to a lesser extent on ADHD and tic disorders, whereas research for other diagnoses is selective or absent.

    “First, most research focuses on autism, and to a lesser extent on ADHD and tic disorders, whereas research for other diagnoses is selective or absent.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Beyond specific genetic syndromes such as FXS, there is little research on sex/gender effects in intellectual disabilities, which is also reflected in the autism literature insofar as autistic people with intellectual disabilities are disproportionately under-represented.

    “Beyond specific genetic syndromes (for example, FXS), there is little research on sex/gender effects in intellectual disabilities, which is also reflected in the autism literature insofar as autistic people with intellectual disabilities are disproportionately under-represented304,305.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [304] Russell, G. et al. Selection bias on intellectual ability in autism research: a cross-sectional review and meta-analysis. Mol. Autism 10, 9 (2019). source

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    • cites [305] Thurm, A. et al. Making research possible: barriers and solutions for those with ASD and ID. J. Autism Dev. Disord. 52, 4646–4650 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In ADHD, hyperactivity, impulsivity and inattentive patterns change over the course of development, and research published over the last two decades has proposed a potential late-onset form, although this remains controversial.

    “In ADHD, hyperactivity, impulsivity and inattentive patterns change over the course of development, and research published over the last two decades has proposed the existence of a potential ‘late-onset’ form, although this remains controversial25,27,307,308.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [25] Sibley, M. H. et al. Late-onset ADHD reconsidered with comprehensive repeated assessments between ages 10 and 25. Am. J. Psychiatry 175, 140–149 (2018). source

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    • cites [27] Asherson, P. & Agnew-Blais, J. Annual research review: does late-onset attention-deficit/hyperactivity disorder exist? J. Child Psychol. Psychiatry 60, 333–352 (2019). source

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    • cites [307] Willcutt, E. G. et al. Validity of DSM-IV attention deficit/hyperactivity disorder symptom dimensions and subtypes. J. Abnorm. Psychol. 121, 991–1010 (2012). source

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    • cites [308] Taylor, L. E., Kaplan-Kahn, E. A., Lighthall, R. A. & Antshel, K. M. Adult-onset ADHD: a critical analysis and alternative explanations. Child Psychiatry Hum. Dev. 53, 635–653 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Typically, larger sex/gender differences are reported in clinical studies, but infrequently the same patterns emerge in population-based studies.

    “Typically, larger sex/gender differences are reported in clinical studies, but infrequently the same patterns emerge in population-based studies78,82–84.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [78] Lai, M. C. et al. Prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis. Lancet Psychiatry 6, 819–829 (2019). source

      Not checked in the free run.

    • cites [82] Ottosen, C. et al. Sex differences in comorbidity patterns of attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 58, 412–422 (2019). source

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    • cites [83] Simonoff, E. et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J. Am. Acad. Child Adolesc. Psychiatry 47, 921–929 (2008). source

      Not checked in the free run.

    • cites [84] Martin, J. et al. Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: investigating genetic liability and comorbidity. Am. J. Med. Genet. B Neuropsychiatr. Genet. 186, 412–422 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This is especially the case for those with high support needs, whose pronounced cognitive and/or language impairments necessitate round-the-clock care, that is, so-called profound autism.

    “This is especially the case for those with high support needs, whose pronounced cognitive and/or language impairments necessitate round-the-clock care, that is, so-called profound autism73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Lord, C. et al. The Lancet Commission on the future of care and clinical research in autism. Lancet 399, 271–334 (2022). source

      Not checked in the free run.

89 of 89

  • The paper relies on this without support.

    Sex/gender moderation effects on brain structure and function in non-syndromic intellectual disabilities remain largely unexplored.

    “Sex/gender moderation effects on brain structure and function in non-syndromic intellectual disabilities remain largely unexplored.”

  • The paper relies on this without support.

    Very few countries register sex beyond the male/female binary and gender identity.

    “and there are very few countries that register sex beyond the male/female binary and gender identity.”

  • The paper relies on this without support.

    Most research focuses on autism, and to a lesser extent on ADHD and tic disorders, whereas research for other diagnoses is selective or absent.

    “First, most research focuses on autism, and to a lesser extent on ADHD and tic disorders, whereas research for other diagnoses is selective or absent.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Although the male-to-female ratio in this review of about 3:1 is largely representative of neurodevelopmental conditions, the small numbers make it difficult to know how well results apply beyond males.

    “Although the ratio of males to females in this review (~3:1) is largely representative of neurodevelopmental conditions (Bölte et al., 2023), the small numbers do make it difficult to know how well the results specifically apply beyond males.”

    From Cognitive Profile in Autism and ADHD: A Meta-Analysis of Performance on the WAIS-IV and WISC-V (2024) · cites this paper as Bölte et al., 2023

The citation lists haven’t been fetched yet

References 368 · Cited by 249

Research works printed but not linked: 4

  1. Lanzenberger, R., Kranz, G. S. & Savic, I. (eds) Sex Differences in Neurology and Psychiatry (Elsevier, 2020). [Series Eds Aminoff, M. J., Boller, F. & Swaab, D. F. Handbook of Clinical Neurology Vol. 175]
  2. Bölte, S., Poustka, L. & Geurts, H. M. in Oxford Textbook of Attention Deficit Hyperactivity Disorder Ch. 24 (eds Banaschewski, T., Coghill, D. & Zuddas, A.) 227–234 (Oxford Univ. Press, 2018).
  3. Greven, C. U., Richards, J. S. & Buitelaar, J. K. in Oxford Textbook of Attention Deficit Hyperactivity Disorder Ch. 16 (eds Banaschewski, T., Coghill, D. & Zuddas, A.) 154–160 (Oxford Univ. Press, 2018).
  4. Gillespie-Lynch, K. et al. in Disability Alliances and Allies Vol. 12 (eds Carey, A. C., Ostrove, J. M. & Fannon, T.) 189–223 (Emerald, 2020).

Authors
Bölte, S., Neufeld, J., Marschik, P. B., Williams, Z. J., Gallagher, L., & Lai, M.-C.
Affiliations
  • Curtin University (AU)
  • Swedish Collegium for Advanced Study (SE)
  • Medical University of Graz (AT)
  • Vanderbilt University (US)
  • Centre for Addiction and Mental Health (CA)
Corresponding author
Bölte, Sven
ORCID
Venue
Nature Reviews Neurology
Publisher
Springer Science and Business Media LLC
Published
2023-02-06
Volume
19
Issue
3
Pages
136-159
ISSN
  • 1759-4758 (ISSN-L)
  • 1759-4766
DOI
10.1038/s41582-023-00774-6
PMC
PMC10154737
OpenAlex
W4319334505
Cited by
249
References
368
Citations by year
2026: 71 · 2025: 81 · 2024: 63 · 2023: 34
FWCI
12.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (456967546)
  • University of Toronto
  • Karolinska Institutet
  • Department of Psychiatry, University of Toronto
  • Canadian Institutes of Health Research (GSB 17137 3)
  • National Institute on Deafness and Other Communication Disorders (F30DC019510)
  • National Institute of General Medical Sciences (T32GM007347, GM-007347)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
sex differences, gender identity, neurodevelopmental disorders, autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability
MeSH terms
Attention Deficit Disorder with Hyperactivity, Female, Gender Identity, Humans, Male, Intellectual Disability, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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