CoChat
Sign Up
Cited by 1,280Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersSexual Differentiation and Disorders

Sex differences in autism spectrum disorders

Open access
Werling, Donna M., Geschwind, Daniel H.·2013·Current Opinion in Neurology
DOI 10.1097/wco.0b013e32835ee548PMC PMC4164392
Open this paper in CoChat — free account

Abstract

PURPOSE OF REVIEW: A strong male bias in autism spectrum disorder (ASD) prevalence has been observed with striking consistency, but no mechanism has yet to definitively account for this sex difference. This review explores the current status of epidemiological, genetic, and neuroendocrinological work addressing ASD prevalence and liability in males and females, so as to frame the major issues necessary to pursue a more complete understanding of the biological basis for sex-differential risk. RECENT FINDINGS: Recent studies continue to report a male bias in ASD prevalence, but also suggest that sex differences in phenotypic presentation, including fewer restricted and repetitive behaviors and externalizing behavioral problems in females, may contribute to this bias. Genetic studies demonstrate that females are protected from the effects of heritable and de-novo ASD risk variants, and compelling work suggests that sex chromosomal genes and/or sex hormones, especially testosterone, may modulate the effects of genetic variation on the presentation of an autistic phenotype. SUMMARY: ASDs affect females less frequently than males, and several sex-differential genetic and hormonal factors may contribute. Future work to determine the mechanisms by which these factors confer risk and protection to males and females is essential.

Integrity signals

Registry

Crossref · 10.1097/wco.0b013e32835ee548

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 134 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    High sex ratios have been found by studies that predominantly identified subjects via treatment facilities or disability registries.

    “Generally, high sex ratios have been found by studies that predominantly identified subjects via treatment facilities or disability registries [8,9,14], including more recent studies of records from Boston area hospital records [15*] and Taiwanese disability registries [16*].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [8] Volkmar FR Szatmari P Sparrow SS Sex differences in pervasive developmental disorders J Autism Dev Disord 1993 23 4 579 91 8106301 source

      Not checked in the free run.

    • cites [9] Yeargin-Allsopp M Rice C Karapurkar T Prevalence of autism in a US metropolitan area JAMA 2003 289 1 49 55 12503976 source

      Not checked in the free run.

    • cites [14] Lord C Schopler E Differences in sex ratios in autism as a function of measured intelligence J Autism Dev Disord 1985 15 2 185 93 3997745 source

      Not checked in the free run.

    • cites [15*]

      Not checked in the free run.

    • cites [16*]

      Not checked in the free run.

  • Interpretationreasoning

    Sex differences in phenotypic presentation, such as fewer restricted and repetitive behaviors and externalizing problems in females, may contribute to the male bias in ASD prevalence.

    “sex differences in phenotypic presentation, including fewer restricted and repetitive behaviors and externalizing behavioral problems in females, may contribute to this bias.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Several sex-differential genetic and hormonal factors may contribute to the sex difference in ASD.

    “several sex-differential genetic and hormonal factors may contribute.”
    • Also stated in: § Conclusion · hedged
      “still other sex-differential genetic and hormonal factors acting to potentiate risk to males and/or attenuate risk to females”
    Quote in the paperSubstantial claim
  • Premisenone given

    Females are protected from the effects of heritable and de novo ASD risk variants.

    “Genetic studies demonstrate that females are protected from the effects of heritable and de novo ASD risk variants”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Among individuals who meet diagnostic criteria for ASD, females are not more severely affected than males.

    “This suggests that among those who meet diagnostic criteria, females are not more severely affected.”
    Quote in the paperSubstantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 36

  • May combine two claims.

    Interpretationreasoning

    Co-morbid ID increases females' likelihood of acquiring an ASD diagnosis, and high-functioning females may go undiagnosed.

    “Co-morbid ID increases females’ likelihood of acquiring an ASD diagnosis, and conversely high-functioning females may go undiagnosed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A 1999 review reported median sex ratios of 6:1 among normal-functioning subjects and 1.7:1 among cases with moderate to severe ID.

    “a 1999 review reported median sex ratios of 6:1 among normal-functioning subjects and 1.7:1 among cases with moderate to severe ID [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Fombonne E The epidemiology of autism: a review Psychol Med 1999 29 4 769 86 10473304 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The wide variation in sex ratio across ADDM Network sites and the finding that clinically ascertained samples show higher M:F ratios than population screening in South Korea are consistent with the ascertainment bias hypothesis.

    “The wide variation in the sex ratio reported by different sites in the Autism and Developmental Disabilities Monitoring (ADDM) Network and findings from large-scale population screening for ASD in a South Korean community where clinically ascertained samples show higher M:F ratios than less biased population screening are consistent with this hypothesis [12**,13**].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12**,13**]

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The extent of the male over-representation in ASD and the degree to which it relates to intellectual functioning or ascertainment methods are currently not understood.

    “we currently do not understand the extent of this over-representation, or the degree to which this male bias in prevalence is related to intellectual functioning or ascertainment methods in addition to the influence of sex-differential genetic or hormonal factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intelligence level affects the sex ratio in ASD: males are substantially over-represented among high-functioning cases, and males and females are more equally represented among cases with severe intellectual disability.

    “Intelligence level affects this sex ratio: males are substantially over-represented among high-functioning cases, and males and females are more equally represented among cases with severe intellectual disability (ID) [8,9,10,11]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Volkmar FR Szatmari P Sparrow SS Sex differences in pervasive developmental disorders J Autism Dev Disord 1993 23 4 579 91 8106301 source

      Not checked in the free run.

    • cites [9] Yeargin-Allsopp M Rice C Karapurkar T Prevalence of autism in a US metropolitan area JAMA 2003 289 1 49 55 12503976 source

      Not checked in the free run.

    • cites [10] Banach R Thompson A Szatmari P Brief Report: Relationship between non-verbal IQ and gender in autism J Autism Dev Disord 2009 39 1 188 93 18594959 source

      Not checked in the free run.

    • cites [11] Fombonne E The epidemiology of autism: a review Psychol Med 1999 29 4 769 86 10473304 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Males with ASD show more externalizing behavior problems than females, including aggressive behavior, hyperactivity, reduced prosocial behavior, and increased repetitive/restricted behaviors and interests.

    “Males with ASD are found to show more externalizing behavior problems than females, such as aggressive behavior, hyperactivity, reduced prosocial behavior, and increased repetitive/restricted behaviors and interests [24*,25*,26**,27*,28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24*,25*,26**,27*,28]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A higher proportion of female ASD cases carry a de novo CNV than male cases, and these CNVs disrupt a greater number of genes than those from males.

    “studies of chromosomal structural variation that indicate that a higher proportion of female cases carry a de novo CNV than male cases and that these CNVs disrupt a greater number of genes than those from males [45,46*,47*].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45,46*,47*]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In combination with the presence of a Y chromosome, this lack of paternal X expression could raise ASD risk for both KS and XYY syndromes, and for a higher proportion of XYY cases as observed.

    “In combination with the presence of a Y chromosome, this lack of paternal X expression could then raise ASD risk for both syndromes, and for a higher proportion of XYY cases as is observed.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: 40-50% of Klinefelter syndrome cases arise from maternal nondisjunction of the X chromosome.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Fetal testosterone levels may drive cognitive hypermasculinization in ASD.

    “Baron-Cohen and colleagues have proposed that fetal testosterone (FT) levels may also drive cognitive hypermasculinization in ASD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ASD-diagnosed girls had a higher mean total problem score and a higher frequency of low IQ than ASD-diagnosed boys.

    “ASD-diagnosed girls had a higher mean total problem score (hyperactivity, anxiety, and conduct, peer, and prosocial problems) and a higher frequency of low IQ than ASD-diagnosed boys.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30**]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only the male-only linkage signal at 17q21 has been successfully replicated, and the exact risk genes or variants responsible for these linkage peaks remain unknown.

    “only the male-only linkage signal at 17q21 has been successfully replicated, and the exact risk genes or variants responsible for these linkage peaks remain unknown.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [35] Stone JL Merriman B Cantor RM Evidence for sex-specific risk alleles in autism spectrum disorder Am J Hum Genet 2004 75 6 1117 23 15467983 PMC1182147 source

      Not checked in the free run.

    • cites [36] Cantor RM Kono N Duvall JA Replication of autism linkage: fine-mapping peak at 17q21 Am J Hum Genet 2005 76 6 1050 6 15877280 PMC1196442 source

      Not checked in the free run.

    • cites [37] Szatmari P Paterson AD Zwaigenbaum L Mapping autism risk loci using genetic linkage and chromosomal rearrangements Nat Genet 2007 39 3 319 28 17322880 PMC4867008 source

      Not checked in the free run.

    • cites [38] Lamb JA Barnby G Bonora E Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects J Med Genet 2005 42 2 132 7 15689451 PMC1735992 source

      Not checked in the free run.

    • cites [39] Schellenberg GD Dawson G Sung YJ Evidence for multiple loci from a genome scan of autism kindreds Mol Psychiatry 2006 11 11 1049 60 16880825 source

      Not checked in the free run.

    • cites [40] Weiss LA Arking DE Daly MJ Chakravarti A A genome-wide linkage and association scan reveals novel loci for autism Nature 2009 461 7265 802 8 19812673 PMC2772655 source

      Not checked in the free run.

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

    Interpretationreasoning

    Male-typical externalizing behaviors may be more disruptive in home or school than female-typical internalizing behaviors, preferentially prompting evaluation and diagnosis for boys, especially high-functioning girls.

    “The observed sex differences raise the possibility that male-typical externalizing behaviors are more disruptive in the home or school setting than female-typical internalizing behaviors, preferentially prompting evaluation and diagnosis for boys, especially as compared to high-functioning girls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High-functioning ASD cases scored lower than typical males on measures of empathy and friendship, and higher than typical males on measures of systemizing.

    “In these studies, high-functioning ASD cases scored lower than typical males on measures of empathy and friendship, and higher than typical males on measures of systemizing.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [61] Baron-Cohen S Wheelwright S The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences J Autism Dev Disord 2004 34 2 163 75 15162935 source

      Not checked in the free run.

    • cites [62] Baron-Cohen S Wheelwright S The Friendship Questionnaire: an investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences J Autism Dev Disord 2003 33 5 509 17 14594330 source

      Not checked in the free run.

    • cites [63] Baron-Cohen S Richler J Bisarya D The systemizing quotient: an investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences Philos Trans R Soc Lond B Biol Sci 2003 358 1430 361 74 12639333 PMC1693117 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Whether the male-skewed prevalence of ASD is due to biased diagnosis or true sex differences (or both), sex-specific biology is likely to play a role.

    “Nevertheless, whether the male-skewed prevalence of ASD is due to biased diagnosis of sex-differential presentations of the disease or to true sex differences in prevalence (or both), sex-specific biology is likely to play a role.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Regardless of whether risk variants are inherited or de novo, with comparable genetic liability, males are at increased risk for and females are protected from manifesting ASD symptoms that meet diagnostic criteria.

    “it appears that regardless of whether risk variants are inherited or de novo, in the face of a comparable degree of genetic liability, males are at increased risk for and females are protected from manifesting ASD symptoms that meet diagnostic criteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Levels of testosterone and its precursors were significantly elevated in a sample of ASD cases, with 57 of 70 subjects having at least one androgen metabolite above the upper limit of sex- and age-matched reference ranges.

    “levels of testosterone and its precursors were found to be significantly elevated in a sample of ASD cases, with 57 of the 70 subjects having at least one androgen metabolite measuring above the upper limit of sex- and age-matched reference ranges [69].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Geier DA Geier MR A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies Neuro Endocrinol Lett 2007 28 5 565 73 17984958

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing FT correlates with increased volume of the right temporoparietal junction/posterior superior temporal sulcus and decreased volume of the planum temporale/parietal operculum and posterior lateral orbitofrontal cortex.

    “Recent work has even found a correlation between increasing FT and volume of sexually dimorphic brain regions, specifically increased volume of the right temporoparietal junction/posterior superior temporal sulcus and decreased volume of the planum temporale/parietal operculum and posterior lateral orbitofrontal cortex volume [68*].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68*]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A study of rare CNVs identified the first inherited autosomal variant with clear male-biased penetrance: males carrying a microdeletion in SHANK1 had high-functioning autism, while female relatives carrying the same microdeletion showed anxiety but did not meet diagnostic criteria for ASD.

    “a study of rare copy number variants (CNVs) in ASD identified the first inherited autosomal variant with clear male-biased penetrance: males carrying a microdeletion in SHANK1 had high-functioning autism, while female relatives carrying the same microdeletion showed anxiety but did not meet diagnostic criteria for ASD [42**].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42**]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies have failed to support the genetic loading hypothesis, including a study of 882 families and a study of high-risk siblings.

    “other studies have failed to support the genetic loading hypothesis, including a study of 882 families [33] and another recent study of high risk siblings of autistic probands that found that only the sex of the sibling was a significant predictor of their future ASD status [34**].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Goin-Kochel RP Abbacchi A Constantino JN Lack of evidence for increased genetic loading for autism among families of affected females: a replication from family history data in two large samples Autism 2007 11 3 279 86 17478580 source

      Not checked in the free run.

    • cites [34**]

      Not checked in the free run.

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

    Premisecitation

    The Extreme Male Brain theory proposes that ASD arises from hypermasculinization of the brain.

    “One major theory that invokes a broad role for testosterone in ASD etiology is the Extreme Male Brain theory, which proposes that ASD arises from hypermasculinization of the brain [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Baron-Cohen S The extreme male brain theory of autism Trends Cogn Sci 2002 6 6 248 254 12039606 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These observations suggest that the Y chromosome is a risk factor for ASD and that a second X chromosome is protective, possibly via genes that escape X-inactivation.

    “these observations suggest several intriguing possibilities: 1) the Y chromosome is a risk factor for ASD, and 2) a second X chromosome is protective, possibly via genes that escape X-inactivation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Under the multiple-threshold model, females with ASD are likely to carry a higher heritable mutational load than affected males.

    “genetic studies operating under this model hypothesize that females with ASD are likely to be carrying a higher heritable mutational “load” than affected males.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Reich R Cloninger CR Guze SB The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry Br J Psychiatry 1975 127 1 10 1139078 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Girls without diagnoses showed increased communication difficulties but reduced social impairments compared to non-diagnosed boys.

    “Girls without diagnoses showed increased communication difficulties, but reduced social impairments as compared to non-diagnosed boys.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30**]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sex chromosome aneuploidies are associated with increased rates of ASD diagnosis in Turner syndrome (~3%), Klinefelter syndrome (~10%), and 47,XYY syndrome (~20%), but not in X chromosome trisomy.

    “with an increased rate of ASD diagnosis in Turner syndrome (TS, XO, ~3% ASD) [52,53,54], Klinefelter syndrome (KS, XXY, ~10% ASD) [55,56*], and 47,XYY syndrome (~20% ASD), but no increased rate in X chromosome trisomy [57,58**].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [52] Donnelly SL Wolport CM Menold MM Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome Am J Med Genet 2000 96 3 312 6 10898907 source

      Not checked in the free run.

    • cites [53] Skuse DH James RS Bishop DV Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function Nature 1997 387 6634 705 8 9192895 source

      Not checked in the free run.

    • cites [54] Creswell C Skuse D Autism in association with Turner syndrome: Genetic implications for male vulnerability to pervasive developmental disorders Neurocase 1999 5 511 518 source

      Not checked in the free run.

    • cites [55,56*]

      Not checked in the free run.

    • cites [57,58**]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RORA regulates expression of aromatase, the enzyme that converts androgens to estrogens, and is reciprocally activated by estradiol and inhibited by testosterone.

    “RORA regulates expression of aromatase, the enzyme that converts androgens to estrogens, and is reciprocally activated by estradiol and inhibited by testosterone [75*].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75*]

      Not checked in the free run.

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

    Premisecitation

    The clinical sample in Kohane et al. had a male-to-female ratio of 3.84.

    “3.84 M:F also reported for this clinical sample”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Taiwanese government registry, ASD cases were more prevalent in males, with a male-to-female ratio near 6:1.

    “ASD cases documented in Taiwanese government registry found to be more prevalent in males (M:F near 6:1)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

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

    Premisecitation

    Kim et al. performed the initial population screening for ASD prevalence among children in South Korea.

    “The first population screening for ASD prevalence in children in South Korea.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

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

    Premisecitation

    Kohane et al. estimated co-morbidity prevalence on a large scale using 14,000 ASD cases from retrospective hospital records.

    “Large-scale prevalence estimates for co-morbidities in 14,000 ASD cases from retrospective examination of hospital records”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The higher proportion of high functioning female ASD cases may be due to rigorous surveillance of ASD symptoms in this sample.

    “possibly due to the rigorous surveillance of ASD symptoms in this sample”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] source

      Not checked in the free run.

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

    Premisecitation

    The US CDC 2012 report found an overall ASD prevalence of 1 in 88 (1.1%), an increase from 1 in 110 in 2009.

    “reporting an overall prevalence of 1 in 88 (1.1%), up from 1 in 110 in 2009”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

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

    Premisecitation

    A study of unaffected Japanese adults found no correlation between salivary testosterone levels and autistic-like traits.

    “although a study of unaffected Japanese adults found no correlation between salivary testosterone levels and autistic-like traits [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Takagishi H Takahashi T Yamagishi T Salivary testosterone levels and autism-spectrum quotient in adults Neuro Endocrinol Lett 2010 31 6 837 41 21196912

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ASD risk is likely multifactorial, with many genetic variants and environmental factors contributing to liability, and sex-differential genetic and hormonal factors acting to potentiate risk to males and/or attenuate risk to females.

    “ASD risk is likely to be multifactorial, with many different genetic variants and environmental factors contributing to liability, and still other sex-differential genetic and hormonal factors acting to potentiate risk to males and/or attenuate risk to females (Figure 1B).”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    These regulatory relationships may create a feedback loop that further elevates testosterone levels.

    “These regulatory relationships may create a feedback loop that further elevates testosterone levels”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The role of the hormonal milieu in ASD liability is likely complex and may be mediated by other risk factors.

    “hypogonadism in XXY males in the face of a nearly 10-fold increase in ASD prevalence suggests that the role of the hormonal milieu in ASD liability is likely complex and may be mediated by other risk factors.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Among 777 children, only IQ and age significantly affected ASD severity when considering IQ, age, SES, sex, and race.

    “Examination of the relationship between IQ, age, SES, sex, and race and autistic symptoms in 777 children, only IQ and age are found to have significant effects on ASD severity”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The South Korean population screening found an overall ASD prevalence of 2.64%, higher than expected.

    “finding a higher-than-expected rate of ASDs overall (2.64%)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

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

    Premisecitation

    The US CDC 2012 report is the most recent report on ASD prevalence.

    “The most recent report from the US CDC on ASD prevalence”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings support the multiple threshold model for ASD liability, in which affected females have a higher genetic liability.

    “supporting the multiple threshold model for ASD liability in which affected females have a higher genetic liability”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

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

    Premisecitation

    The English population-based survey found a male-to-female ratio of 9:1.

    “and M:F of 9:1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Evidence suggests that sex chromosomal gene dosage and sex hormone levels may be involved in setting sex-specific liability thresholds.

    “Evidence suggests that sex chromosomal gene dosage and sex hormone levels may be involved in setting sex-specific liability thresholds”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The South Korean population screening identified a high proportion of autistic females in a general non-clinical sample, with a male-to-female ratio of 2.5:1.

    “identified a high proportion of autistic females in a general population (non-clinical) sample (M:F 2.5:1)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

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

    Premisecitation

    The Finnish population screening found a low male-to-female ratio of 2:1.

    “and a low M:F of 2:1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gonadal dysgenesis is common in TS and KS, causing abnormally low postnatal estrogen and testosterone levels, respectively, whereas testosterone levels are normal prenatally in KS and throughout life in 47,XYY cases.

    “gonadal dysgenesis is common in TS and KS, causing abnormally low postnatal estrogen and testosterone levels, respectively, whereas testosterone levels are normal prenatally in KS and throughout life in 47,XYY cases [79,80].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Price WH van der Molen HJ Plasma testosterone levels in males with the 47,XYY karyotype J Endocrinol 1970 47 1 117 22 5428907 source

      Not checked in the free run.

    • cites [80] Ratcliffe SG Read G Pan H Prenatal testosterone levels in XXY and XYY males Horm Res 1994 42 3 106 9 7995613 source

      Not checked in the free run.

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

    Premisecitation

    In the Taiwanese government registry, ASD cases were more prevalent in urban areas, with an urban-to-rural ratio of about 2.5:1.

    “and in urban areas (urban:rural about 2.5:1)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

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

    Premisecitation

    In an English population-based survey of adults living in households, ASD prevalence was 0.98%.

    “Population-based survey for ASDs among adults living in households (non-institutionalized) in England finds prevalence of 0.98%”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

      Not checked in the free run.

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

    Premisecitation

    Hallmayer et al. performed a large, recent, population-based twin study on ASD concordance.

    “A recent, large, population-based twin study of ASD concordance”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

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

    Premisecitation

    They reported about 60% concordance for monozygotic twins and about 25% for dizygotic twins.

    “Findings of ~60% concordance rate in monozygotic and ~25% concordance in dizygotic twin pairs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

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

    Premisecitation

    In males, fetal testosterone levels correlate with the size of brain regions known to be sexually dimorphic.

    “Correlation of males’ fetal testosterone level with volume of brain regions found to be sexually dimorphic in size from a large data set of structural MRI images of brains from male and female children”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] source

      Not checked in the free run.

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

    Premisecitation

    Sato et al. found the first autosomal ASD risk variant showing clear male-specific penetrance.

    “The first identified autosomal risk variant for ASD with clear male-specific penetrance”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] source

      Not checked in the free run.

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

    Premisecitation

    The highest autistic trait rate, 50% among 26 subjects, occurred in 47,XYY cases.

    “with the highest rate (50% of 26 subjects) in 47,XYY cases”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] source

      Not checked in the free run.

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

    Premisecitation

    The 47,XYY group had more severe behavioral problems.

    “Behavioral problems were also found to be more severe in the 47,XYY group”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    They found multiple CNV events recurring independently across unrelated cases.

    “finding several CNV events that recur independently in unrelated cases”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

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

    Premisecitation

    Sanders et al. identified rare, de novo CNVs in sporadic ASD cases.

    “This study identifies rare, de novo CNVs in sporadic ASD cases”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

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

    Premisecitation

    They found a few genes recurrently affected by these rare variants.

    “finding a handful of genes that are recurrently hit by these rare variants”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] source

      Not checked in the free run.

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

    Interpretationcitation

    This supports a role for these rare variants in ASD risk.

    “supports a role for these rare variants in ASD risk”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    These findings suggest a significant role for the gestational environment in ASD susceptibility.

    “and suggest that the gestational environment play a significant role in ASD susceptibility”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

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

    Premisecitation

    Among Klinefelter syndrome cases, autistic trait presentation negatively correlates with a cognitive flexibility measure.

    “Finds a negative correlation between presentation of autistic traits and a measurement of cognitive flexibility in cases with Klinefelter syndrome”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] source

      Not checked in the free run.

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

    Premisecitation

    A possible link exists between these behaviors and executive function task performance.

    “and a potential association between these behaviors and performance on executive function tasks”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] source

      Not checked in the free run.

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

    Premisecitation

    Levy et al. found rare de novo CNVs in sporadic autism cases from almost 1000 simplex families.

    “Identification of rare, de novo CNVs in sporadic autistic cases from nearly 1000 simplex families”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] source

      Not checked in the free run.

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

    Interpretationcitation

    These findings have recalibrated heritability estimates for ASD.

    “have recalibrated heritability estimates for ASD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sibling recurrence rates were 26.2% for males and 9.1% for females, independent of the older autistic sibling's sex.

    “recurrence rate in siblings is 26.2% for males and 9.1% for females, regardless of the sex of their older autistic sibling”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] source

      Not checked in the free run.

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

    Premisecitation

    A prospective study reported an 18.7% recurrence risk among siblings of autistic probands.

    “Prospective study finds a recurrence risk of 18.7% for siblings of autistic probands”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    This implicates specific CNV loci in ASD liability.

    “thereby implicating specific CNV loci in ASD liability”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Males carrying a SHANK1 microdeletion have autism, whereas related female carriers do not have ASD.

    “males with a microdeletion in SHANK1 are autistic, while related female carriers are not affected with ASD”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to parental reports, females with ASDs show more internalizing behaviors and depressive symptoms than males.

    “Parental accounts report a greater degree of internalizing behaviors and depressive symptoms in females than males with ASDs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

      Not checked in the free run.

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

    Premisecitation

    Two ASD-associated co-expression modules may reflect expression changes from primary genetic risk effects and secondary downstream pathophysiology.

    “and two ASD-associated co-expression modules that may represent expression changes caused by primary effects of genetic risk, and secondary effects of downstream pathophysiology”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone activates RORA transcription, while estrogen inhibits it.

    “transcription of RORA is activated by testosterone and inhibited by estrogen”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] source

      Not checked in the free run.

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

    Premisecitation

    RORA stimulates expression of aromatase.

    “and RORA stimulates expression of aromatase”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RORA, a gene downregulated in ASD, plays an integral role in sex hormone metabolism.

    “Finding of integral role for RORA, a gene downregulated in ASD, in sex hormone metabolism”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] source

      Not checked in the free run.

70 of 70

  • The paper relies on this without support.

    ASD transmission in most families does not follow an X-linked pattern.

    “ASD transmission in most families does not follow an X-linked pattern”

  • The paper relies on this without support.

    Several ASD risk genes on the X chromosome all cause significant intellectual disability.

    “while several ASD risk genes have been identified on the X chromosome (e.g. FMRP, MECP2, NLGN3, NLGN4X), all cause significant ID”

  • The paper relies on this without support.

    40-50% of Klinefelter syndrome cases arise from maternal nondisjunction of the X chromosome.

    “Since 40-50% of KS cases arise from maternal nondisjunction of the X”

  • The paper relies on this without support.

    RORA has a role in cerebellar and Purkinje cell development and in neuroprotection from oxidative stress.

    “since RORA has a role in cerebellar and Purkinje cell development, and neuroprotection from oxidative stress.”

  • The paper relies on this without support.

    Sex chromosomal abnormalities frequently affect gonadal function.

    “sex chromosomal abnormalities frequently affect gonadal function.”
5 of 5

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?

  • There are clinical differences between boys and girls with ASD: more externalizing behavior in boys and more internalizing symptoms in girls.

    “There are also several clinical differences between boys and girls with ASD: more externalizing behavior (e.g., aggressive outbursts, social impairment, hyperactivity, restricted behaviors and interests) in boys and more internalizing symptoms in girls (e.g., depression, anxiety, emotional symptoms) (37).”

    From Where Sex Meets Gender: How Sex and Gender Come Together to Cause Sex Differences in Mental Illness (2022) · cites this paper as [37]

  • There is a current lack of consideration of demonstrated age-dependent sex differences in symptomatology related with impairments in social communication and interaction, expressive behaviour, reciprocal conversation, and non-verbal gestures for diagnostic purposes in autistic spectrum disorder.

    “There is a current lack of consideration of the demonstrated age-dependent sex differences in the symptomatology related with impairments in social communication and interaction, expressive behaviour, reciprocal conversation, non-verbal gestures for diagnostic purposes123.”

    From Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare (2020) · cites this paper as [123]

  • There is little evidence that siblings of female probands exhibit a differential risk for the occurrence of categorical ASD.

    “There is little evidence, however, that siblings of female probands exhibit a differential risk for the occurrence of categorical ASD [8, 21, 23–25].”

    From Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study (2015) · cites this paper as [21]

  • Girls with ASD may have a higher threshold for the impact of the multifactorial array of genetic and environmental factors thought to be responsible for ASD.

    “and may have a higher threshold for the impact of the multifactorial array of genetic and environmental factors thought to be responsible for ASD [21].”

    From Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study (2015) · cites this paper as [21]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Opposite hormone effects on RORA are reported

    Minor

    The main text says estradiol activates RORA and testosterone inhibits it, while the description of reference 75 says testosterone activates RORA and estrogen inhibits it. These opposing directions affect the proposed hormone-feedback mechanism.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Kanner, 1943, Nervous Child, 2, 217
  2. 2012, MMWR Surveill Summ, 61, 1
  3. Dworzynski, 2012, sychiatry, 51, 788
  4. Geier, 2007, Neuro Endocrinol Lett, 28, 565
  5. Takagishi, 2010, Neuro Endocrinol Lett, 31, 837

Cited by

Sorted by citations

Related

Authors
Werling, D. M., & Geschwind, D. H.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Geschwind, Daniel H.
ORCID
Venue
Current Opinion in Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2013-04
Volume
26
Issue
2
Pages
146-153
ISSN
1350-7540 (ISSN-L)
DOI
10.1097/wco.0b013e32835ee548
PMC
PMC4164392
OpenAlex
W2087547434
Semantic Scholar
bbd81fd1f3129ff84b20eda96b5e62667cf4239d
Cited by
1,245
References
83
Citations by year
2026: 85 · 2025: 95 · 2024: 109 · 2023: 125 · 2022: 119 · 2021: 144 · 2020: 161 · 2019: 92 · 2018: 89 · 2017: 82 · 2016: 48 · 2015: 47 · 2014: 27 · 2013: 20 · 2012: 2
FWCI
4.06
Type
journal article
Language
en
Open access
Locations
  • Current Opinion in Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (F31MH093086)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
autism spectrum disorder, sex differences, sex differences in phenotype, restricted and repetitive behaviors, externalizing problems, de novo mutations, sex chromosome genes, sex hormones, testosterone, neuroendocrinology, genetic risk
MeSH terms
Child, Child Development Disorders, Pervasive, Female, Humans, Male, Sex Characteristics

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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 ›

Are you an author, or do you see a problem with this page? Request a review