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

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.

[1]  D. Nickerson,et al.  Utilizing Graph Theory to Select the Largest Set of Unrelated Individuals for Genetic Analysis , 2013, Genetic epidemiology.

[2]  Niklas Krumm,et al.  Transmission disequilibrium of small CNVs in simplex autism. , 2013, American journal of human genetics.

[3]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010, Nature.

[4]  Rebecca C. Knickmeyer,et al.  Why Are Autism Spectrum Conditions More Prevalent in Males? , 2011, PLoS biology.

[5]  Gregory M. Cooper,et al.  A Copy Number Variation Morbidity Map of Developmental Delay , 2011, Nature Genetics.

[6]  S. Baron-Cohen.  The extreme male brain theory of autism , 2002, Trends in Cognitive Sciences.

[7]  P. Bolton,et al.  How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? , 2012, Journal of the American Academy of Child and Adolescent Psychiatry.

[8]  E. Fombonne.  Epidemiology of Pervasive Developmental Disorders , 2009, Pediatric Research.

[9]  P. Elliott,et al.  Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus , 2011, Nature.

[10]  J. Goldberg,et al.  Sex differences in repetitive stereotyped behaviors in autism: Implications for genetic liability , 2012, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[11]  H. Kraemer,et al.  Observed Classroom Behavior of Children with ADHD: Relationship to Gender and Comorbidity , 2002, Journal of abnormal child psychology.

[12]  Kenny Q. Ye,et al.  De Novo Gene Disruptions in Children on the Autistic Spectrum , 2012, Neuron.

[13]  J. Golding,et al.  Social and demographic factors that influence the diagnosis of autistic spectrum disorders , 2011, Social Psychiatry and Psychiatric Epidemiology.

[14]  P. Stankiewicz,et al.  Duplication of Xq26.2–q27.1, including SOX3, in a mother and daughter with short stature and dyslalia , 2005, American journal of medical genetics. Part A.

[15]  Allison G. Dempsey,et al.  A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders , 2012, Journal of Medical Genetics.

[16]  Bradley P. Coe,et al.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations , 2012, Nature.

[17]  L. Shaffer,et al.  Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2 , 2008, Clinical genetics.

[18]  S. Bryson,et al.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study , 2011, Pediatrics.

[19]  N. de Leeuw,et al.  X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome , 2013, Human Genetics.

[20]  C. Lord,et al.  The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors , 2010, Neuron.

[21]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[22]  Kathryn Roeder,et al.  Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism , 2011, Neuron.

[23]  J. Mandel,et al.  Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations , 2004, European Journal of Human Genetics.

[24]  J. Brian,et al.  Sex Differences in Children with Autism Spectrum Disorder Identified Within a High-Risk Infant Cohort , 2012, Journal of Autism and Developmental Disorders.

[25]  H. Ropers,et al.  X-linked mental retardation , 2005, Nature Reviews Genetics.

[26]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[27]  Bradley P. Coe,et al.  Estimates of penetrance for recurrent pathogenic copy-number variations , 2012, Genetics in Medicine.

[28]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[29]  Donna M. Martin,et al.  Phenotypic heterogeneity of genomic disorders and rare copy-number variants. , 2012, The New England journal of medicine.

[30]  David W. Evans,et al.  Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence , 2013, The Lancet Neurology.

[31]  Swaroop Aradhya,et al.  An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities , 2011, Genetics in Medicine.

[32]  A. V. Vulto-van Silfhout,et al.  Clinical Significance of De Novo and Inherited Copy‐Number Variation , 2013, Human mutation.

[33]  Richard M Myers,et al.  Population analysis of large copy number variants and hotspots of human genetic disease. , 2009, American journal of human genetics.

[34]  J. Rosenfeld,et al.  Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader–Willi syndrome , 2010, European Journal of Human Genetics.

[35]  J. Constantino,et al.  Lack of evidence for increased genetic loading for autism among families of affected females , 2007, Autism.

[36]  Angelica Ronald,et al.  Examining and interpreting the female protective effect against autistic behavior , 2013, Proceedings of the National Academy of Sciences.

[37]  Michael F. Walker,et al.  De novo mutations revealed by whole-exome sequencing are strongly associated with autism , 2012, Nature.

[38]  Boris Yamrom,et al.  Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders , 2011, Neuron.

[39]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.