Sebastien Jacquemont et al., A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders, The American Journal of Human Genetics 94 (2014)
Small (<400 kb) and rare (<1%) CNVs were equally distributed across gender, but those larger than 400 kb or 1 Mb were significantly enriched in females.
De nove CNVs > 400kb and > 1Mb showed a similar high and significant excess in females.
Parental testing was performed on those 3,561 CNVs highly enriched with deleterious variants. Both diagnostic cohorts showed a significant excess of maternally inherited CNVs.
Maternal inheritance was significantly higher for deleterious CNVs (>400kb or > 1 Mb) than for CNVs < 400 kb.
Rare deleterious variants on the X chromosome account for only a small proportion of the bias observed on the autosomes.
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.
These data bring convincing evidence supporting the “female protective model” in NDs.
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. In this hypothesis, female brains would require larger mutational burden to reach the ASD diagnostic threshold.