title: A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.
abstract: 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.
authors.affiliation: Service of Medical Genetics, University Hospital of Lausanne, University of Lausanne, Lausanne 1011, Switzerland. Electronic address: sebastien.jacquemont@chuv.ch.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland; Swiss institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Micha
authors.initials: M
authors.lastname: Hersch
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Duyzend
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland; Swiss institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Swiss institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Signature Genomic Laboratories LLC, PerkinElmer Inc., Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute. Electronic address: eee@gs.washington.edu.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D022202:Chromosomes, Artificial, Bacterial; D003072:Cognition Disorders / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D055815:Young Adult