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Sex and gender in neurodevelopmental conditions

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.

Key points

  • Sex-related and gender-related factors moderate or mediate biological and behavioural variability in neurodevelopmental conditions; they exert influence through diverse mechanisms that act at multiple levels.

  • Moderating effects of sex and/or gender are supported by epidemiological, behavioural, cognitive, neurobiological, genetic, endocrinological and immunological evidence, especially in autism, but also in attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, dyslexia and fragile X syndrome.

  • In autism and ADHD, research has started to raise awareness of clinical nuances to enable better and earlier identification of neurodivergent females.

  • In neuroimaging studies, the neurobiological correlates of autism and ADHD show some overlap between males and females, but also some qualitative differences; preliminary evidence indicates that there are differences in the presentation of fragile X syndrome, dyslexia and Tourette syndrome in the brain between female and male individuals.

  • Sex hormones are implicated in the mechanisms underlying sex differences in brain development and in susceptibility to neurodevelopmental conditions, but much of the evidence relies on preclinical studies.

  • Future research needs to address under-representation of females, gender minorities and specific diagnoses; challenges of interpretation; insufficient understanding of specific sex and gender attributes; developmental variabilities; intersectionality of ethnocultural and sex/gender factors; and sex/gender influences of intervention.

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Fig. 1: Why are sex and gender important for neurodevelopmental conditions?
Fig. 2: Simplified schema of the influences of sex-related and gender-related attributes on brain development.

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Acknowledgements

The authors thank E.-L. Säätelä and A. Vikingson, Karolinska Institutet Library, for expertise and assistance in the systematic literature search. For this review, J.N. was supported by Riksbankens Jubileumsfonds as a Pro-Futura Scientia fellow; P.B.M. was supported by DFG grant 456967546 and VW IDENTIFIED; Z.J.W. was supported by National Institute on Deafness and Other Communication Disorders grant F30-DC019510 and National Institute of General Medical Sciences grant T32-GM007347; and M.-C.L. was supported by the Academic Scholars Award from the Department of Psychiatry, University of Toronto, and the Canadian Institutes of Health Research Sex and Gender Science Chair (GSB 171373).

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Contributions

S.B., J.N., P.B.M., L.G., and M.-C.L. conceptualized and designed the review, based on a systematic literature search led by S.B. These authors divided the focus of their contributions: S.B. (Introduction, Neurodevelopmental conditions, Epidemiology, Behavioural phenotypes, Access and response to interventions, Immunology, Gut–brain axis and microbiome, and Conclusions and future directions), J.N. (Brain biology), P.B.M. (Behavioural phenotypes), L.G. (Genomics, and Sex hormones), M.-C.L. (Sex and gender constructs, Behavioural phenotypes, Access and response to interventions, Conclusions and future directions, boxes, and integration across sections). Z.J.W. particularly examined the work applying community-informed knowledge and neurodiversity-affirmative perspectives. All authors contributed to the writing of the manuscript and revised it critically for important intellectual content. All authors approved the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work was appropriately investigated and resolved.

Corresponding authors

Correspondence to Sven Bölte or Meng-Chuan Lai.

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Competing interests

The authors declare no direct conflict of interest related to this article. S.B. discloses that he has in the last 3 years acted as an author, consultant or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, Kohlhammer and UTB, and editorial honorarium from SAGE Publications. S.B. is a shareholder in NeuroSupportSolutions International and SB Education/Psychological Consulting. P.B.M. has received royalties for textbooks from Springer and Urban & Fischer and editorial honorarium from Elsevier. Z.J.W. has received consulting fees from Autism Speaks, the May Institute, and Roche; he also serves on the Autistic Researchers Review Board of the Autism Intervention Research Network for Physical Health (AIR-P). L.G. has acted as a consultant to Kingdom Therapeutics. M.-C.L. has received editorial honorarium from SAGE Publications.

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Nature Reviews Neurology thanks Stewart Mostofsky, who co-reviewed with Laura Rice; Christine Wu Nordahl, Donna Werling and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Gender diversity

The variations of gender identity and expression in the human populations that may or may not be aligned with those stereotypically linked to a person’s sex assigned at birth.

Gender-minority individual

A person whose gender identity is different from their gender and sex assigned at birth; for instance, someone who identifies as transgender or non-binary.

Genomic imprinting

Parent-of-origin-specific allelic expression of genes whereby only one copy of a gene is expressed while the other copy is suppressed; both maternally and paternally inherited genes can be subject to genomic imprinting.

Impression management

The ubiquitous human tendency to present favourable impressions of oneself in front of others during social interactions, such that one can achieve interpersonal or pragmatic rewards.

Lateralization

The tendency for selective neural or cognitive processes to be more strongly represented in or specialized to one brain hemisphere.

Liabilities

The sum of genetic and environmental factors that contribute to the development of a multifactorial phenotype; the genetic liability threshold model proposes that there is a continuous liability distribution within a population for a binary trait outcome and the distribution has a threshold that divides the population into two (that is, those with and those without the trait).

Morphosyntactic

An alternative term for ‘grammar’; grammar includes morphology and syntax, where morphology is about words and their formation, and syntax is about sentences and their formation.

Mosaicism

In genetics, mosaicism refers to the situation where an individual or organism has more than one genetic lineage within their cells, which can arise secondary to genetic mutation (including sex chromosomes) in the zygote; regarding neurophenotypes, mosaicism refers to the idea that the degree of typical ‘maleness’/‘femaleness’ of specific features in the brain of an individual is not internally consistent.

Profound autism

A new administrative term proposed by The Lancet Commission on the future of care and clinical research in autism to describe autistic individuals with high support needs (that is, requiring 24-h access to an adult who can care for them if concerns arise, being unable to be left completely alone in a residence, and not being able to take care of basic daily adaptive needs), often owing to substantial intellectual disability, very limited language, or both73.

Sex assigned at birth

The sex label (also termed ‘sex at birth’ or ‘sex designated at birth’) recorded at a person’s birth (for example, on a person’s birth certificate), typically given based on a child’s reproductive system and related physical characteristics (for example, genital anatomy).

Sex chromosome aneuploidies

The presence of additional sex chromosome(s) (X or Y) beyond the normal complement, associated with neurogenetic conditions; for example, X0 (Turner syndrome), XXY (Klinefelter syndrome), XXX (trisomy X, triple X syndrome), XYY (XYY syndrome, Jacobs syndrome).

Transdiagnostic methods

Approaches that reduce adherence to the conventional categorical diagnostic nosology or replace it with new frameworks that characterize medical, psychiatric and neurodevelopmental conditions in terms of relevant trait dimensions instead of discrete categories21.

X chromosome inactivation

The random silencing of one copy of the X chromosome per cell in individuals with XX chromosomes to compensate for dosage effects.

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Bölte, S., Neufeld, J., Marschik, P.B. et al. Sex and gender in neurodevelopmental conditions. Nat Rev Neurol 19, 136–159 (2023). https://doi.org/10.1038/s41582-023-00774-6

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