Taking stock of critical clues to understanding sex differences in the prevalence and recurrence of autism

In this issue of Autism, new evidence for the equivalency of symptom burden and structure among males and females affected by autism spectrum disorder (ASD) continues to move the spotlight from a notion that the sex ratio in ASD results from the condition being somehow different between the sexes, to the more likely scenario that males and females categorically differ in their susceptibility to reaching a (common) diagnostic threshold in the setting of pathogenic risk. The consensus reached by these studies, that is, of relative equivalency in symptom structure between diagnosed males and females, across a variety of methods of symptom ascertainment, is particularly compelling given the rigorousness and accumulated sample sizes of the respective study designs. Establishing a benchmark of diagnostic equivalency is a critical anchor for ongoing efforts to understand the biology of differential liability to ASD as a function of sex, which is one of the most profound and pervasive modifiers in this remarkably heterogeneous—and remarkably heritable—group of disorders (see Tick et al., 2016; Werling, 2016). Clearly, elucidation of the nature of sex-specific differences in ASD liability—given that the vast majority of the heritable influence appears to be traceable to autosomes (not sex chromosomes)—carries with it one of the most compelling prospects for potent novel therapeutic interventions on the discovery frontier. It is important to place these findings into the context of what is already known about sex bias in ASD. Five years ago, Constantino and Charman (2012) summarized the accumulated evidence in a commentary on an important epidemiologic observation by Dworzynski et al. (2012) that, at a given absolute threshold for autistic trait burden, boys were more likely than girls to be diagnosed with autism, largely on the basis of comorbid, non-ASD-specific, behavioral abnormalities bringing them to clinical attention (see also Duvekot et al., 2016; Frazier et al., 2014). What had been scientifically established by that time was that subtle sex differences in mean scores for autistic traits observed in the general population could not explain the magnitude of the sex ratio for clinical affectation (see also Øien et al., 2017); that there existed known familial monogenic syndromes (FRX, SHANK1) that exhibited sex-specific reduction in the expression of inherited liability for ASD; that recurrence rates in families were remarkably equivalent for male and female index cases (the absence of the Carter effect for clinical ASD, see Constantino, 2014—this contrasts with an observation of sex-specific variation in quantitative thresholds for the aggregation of subclinical autistic traits, reported by Robinson et al., 2013); that the sex ratio is markedly attenuated (nearly 1:1) for severe ASD syndromes accompanied by intellectual disability and dysmorphism (so-called “complex autism”) and markedly accentuated when exclusively considering ASD syndromes not accompanied by cognitive impairment; and that recurrence ratios were attenuated but not eliminated when using quantitative ratings for affectation standardized by sex as normed thresholds for clinical categorization. It had also been repeatedly observed that a broad array of autistic traits aggregate among the siblings of individuals with ASD, but that the distribution of those traits differed markedly between the sexes—continuously among brothers, dichotomously among sisters—providing evidence for a categorical effect of resilience among females in multiplex ASD-affected families. In the 5 years since that time, there have been some very significant new advances, notably: (1) although underidentification of affected females and the phenomenon of symptomatic “camouflage” in school-aged girls (Dean et al., 2016) remain significant concerns for the delivery of appropriate clinical care and attention to affected females, ascertainment of early diagnosis in the later-born infant siblings of affected individuals (i.e. in systematic, unbiased, prospective designs) reveals the same pronounced 3:1 sex ratio that is universally observed later in childhood and adolescence (Constantino, 2016; Messinger et al., 2015); (2) in stark contrast to the case for intellectual disability, only a tiny proportion of molecular genetic risk for ASD is resolvable to genes on sex chromosomes; (3) a relatively higher mutational burden is observed in affected females than affected males, supporting a “female protective model” in autism and related neurodevelopmental disorders (Jacquemont et al., 2014); (4) circulating prenatal testosterone is an unlikely culprit for sex differences (Eriksson et al., 2016); (5) there is no gene on the X chromosome harboring a singular polymorphic that protects females from ASD in dose-dependent fashion (Gockley et al., 2015), however; (6) X-linked genes controlling secondary Taking stock of critical clues to understanding sex differences in the prevalence and recurrence of autism 704414 AUT0010.1177/1362361317704414AutismConstantino research-article2017