A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders

21.10.2021 19:15
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#1 A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders

A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders

Gender bias has been repeatedly observed in neurodevelopmental disorders (NDs), including neuropsychiatric disorders. Epidemiologic studies in schools and institutions caring for individuals with intellectual disability (ID) have shown a 30%–50% excess of males over females.1 In autism spectrum disorder (ASD), the male-to-female ratio is 4:1. It increases to 7:1 for high-functioning autism and drops to 2:1 for individuals with moderate to severe ID.2 Several studies have attempted to gather evidence in favor of a female protective effect (or male susceptibility because this is a relative concept). In a general-population dizygotic-twin cohort, a recent study showed that the gender of the proband with autistic traits influenced the level of autistic traits in the twin sibling: higher autistic traits were measured in the sibling when the proband was a female.3 This suggests that there is a greater etiological load in female probands and their relatives. Other studies, however, did not observe such findings.

We investigated molecular characteristics associated with the increased male-to-female ratio in individuals referred for NDs. These results make a strong case for an “increased etiological burden” in females with NDs. Our findings show that females systematically carry more neurodevelopmentally deleterious variants than do males. This is true whether individuals (1) are ascertained for NDs or (2) are parents of a proband referred for those symptoms. These findings are robust and were replicated in several CNV data sets. Remarkably, SNV data also showed an excess burden despite smaller sample sizes and a greater difficulty in distinguishing neutral from deleterious SNVs. Combined, these data bring convincing evidence supporting the “female protective model” in NDs.
An increased prevalence in males has been observed across different NDs (ASD, ID, attention deficit hyperactivity disorder,31 etc.), and multiple comorbidities are common in these individuals.32 It is therefore challenging to identify those symptoms, which show a gender-specific liability to mutation and might subsequently be driving more males into the clinic. We explored clinical traits potentially associated with this increase in CNV and SNV burden in females ascertained for ASD in the SSC. As previously observed,24, 33 ascertainment for ASD is associated with lower IQs in females. This difference is more pronounced for PIQ than for VIQ, which also confirms previous observations24, 33 (Table S5). Regression analyses showed that PIQ (and to a lesser extent, VIQ) is associated with CNV burden (and SNV burden in males only) (Tables S4 and S5). PIQ could thus be considered a clinical marker of this increased mutational burden in females. However, the increased CNV and SNV burden in females with ND remains after correction for IQ, suggesting that other phenotypes are associated with this excess burden (Tables S4 and S5). An interpretation of this combined increased mutational burden and lower PIQ in females is that lower cognitive abilities are necessary to push females over the ASD diagnostic or referral threshold. The ascertainment of females with lower IQs results in this excess of mutational burden because IQ is associated with deleterious CNVs.12 It is unknown whether these observations for IQ can be generalized across the different cohorts of NDs given that such clinical data are not available for the Signature Genomics cohort.
We are not implying that this gender bias in mutational burden can account completely for the overall dramatic excess of males in high-functioning ASD. Instead, this study suggests that the male brain requires milder alterations to exhibit ASD. The latter might be the basis for what has been described as the “extreme male brain hypothesis,” in which ASD is an extreme expression of the psychological and physiological attributes of the male brain.34 In this hypothesis, female brains would require larger mutational burden to reach the ASD diagnostic threshold.
Phenotype underlying gender bias has recently been explored in a group of 16p11.2 deletion carriers ascertained for NDs; in this group, male carriers significantly outnumbered their female counterparts by 2-fold (112 males and 56 females).10 Although carriers were fully assessed, the study failed to show that female carriers were differentially affected cognitively and/or behaviorally.10 Our analyses of a series of behavioral phenotypes from the SSC did not reveal additional traits with a significant difference across gender (Table S8).
In addition to investigating biological theories, including differences in genetic liability for NDs,35, 36 researchers have investigated the “social bias” hypothesis related to gender stereotypes in the diagnosis of ND or ASD,33 e.g., for equal severity of autistic traits, boys were more likely to receive an ASD diagnosis than girls in the ALSPAC cohort.37 Although our study did not investigate this hypothesis, the excess of maternally inherited CNVs and SNVs speaks against it. This inheritance bias is again in favor of sex-differential liability to mutation, resulting in lower adaptive skills in males and thus leading to lower parenting and household-management skills. The excess rate of maternal inheritance was reproducible across the different cohorts (ISCA and Signature Genomics) and reasons for ascertainment (ND and autism), and the increase in maternal inheritance between large and small CNVs (OR ≈ 1.4) was similar to the gender bias observed in probands ascertained for NDs. NDs and parenting skills might thus represent two opposite ascertainment criteria (which enrich for and against ND symptoms, respectively), resulting in an equally increased burden in females.

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