ArticleAmerican journal of human genetics2014
A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 324 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
324 citing papers in PubMed, 6 syntheses or guidelines pooled it.
- Does the Extreme Male Brain Hypothesis of Autism Apply More to Females Than Males? A Systematic and Meta-Analytic Approach.Autism research : official journal of the International Society for Autism Research · 2026Pooled it
- Presymptomatic Biological, Structural, and Functional Diagnostic Biomarkers of Autism Spectrum Disorder.Journal of neurochemistry · 2025Pooled it
- CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review.Neurogenetics · 2022Pooled it
- Potential of Salivary Biomarkers in Autism Research: A Systematic Review.International journal of molecular sciences · 2021Pooled it
- Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism.Translational psychiatry · 2020Pooled it
- How has DSM-5 Affected Autism Diagnosis? A 5-Year Follow-Up Systematic Literature Review and Meta-analysis.Journal of autism and developmental disorders · 2020Pooled it
- A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.Genome medicine · 2026Trial
- Article
- Preservation of Higher-Order Cognition in Autistic Females: Evidence from Two Deeply-Phenotyped Cohorts in Hong Kong and the United States.Research square · 2026Article
- Sex Disparities in Autism Spectrum Disorder Among Adolescents in the Western Pacific Region: Insights From Epidemiological Trends and Clinical Sample.Journal of autism and developmental disorders · 2026Article
- Advancing risk gene discovery across the allele frequency spectrum.HGG advances · 2026Review
- Copy number variant analysis by exome sequencing is an effective approach to optimize diagnostic yield for developmental disorders-the DDD-Africa study.European journal of human genetics : EJHG · 2026Article
- The NeuroWES project: lessons learned from comprehensive phenotyping and genetic analysis of neurodevelopmental disorders over a decade.Human genetics · 2026Article
- Understanding Sex and Gender Effects on Autism Spectrum Disorder and Obsessive-Compulsive Disorder: Clinical Presentation and Risk Factors.Biological psychiatry global open science · 2026Review
- Dissociable EEG connectivity patterns reflect the latent general and specific dimensions of ADHD in children and adolescents.European child & adolescent psychiatry · 2026Article
- Prdm15 Deficiency Results in Impaired Hippocampal Neurogenesis and Autism-Like Behaviors.Cellular and molecular neurobiology · 2026Article
- Genetic testing and analysis of 1024 children with global developmental delay or intellectual disability: a single-center cohort study.European journal of pediatrics · 2026Article
- Article
- Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect?Annals of neurology · 2026Article
- Modeling rare coding variation on chromosome X provides insight into the genetics and differential sex prevalence of autism spectrum disorder.medRxiv : the preprint server for health sciences · 2026Article
264 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.