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Am J Hum Genet. 2014 Mar 6;94(3):415-25. doi: 10.1016/j.ajhg.2014.02.001. Epub 2014 Feb 27.

A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.

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Service of Medical Genetics, University Hospital of Lausanne, University of Lausanne, Lausanne 1011, Switzerland. Electronic address:
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland; Swiss institute of Bioinformatics, Lausanne 1015, Switzerland.
Swiss institute of Bioinformatics, Lausanne 1015, Switzerland.
Signature Genomic Laboratories LLC, PerkinElmer Inc., Spokane, WA 99207, USA.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute. Electronic address:


Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.

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