Sex-specific penetrance in autosomal dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1 R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Autism Research Center Peking University Health Science Center Beijing 100191 China

Baylor College of Medicine Department of Molecular and Human Genetics Houston TX USA

Baylor Genetics Houston TX USA

Broad Institute of MIT and Harvard Cambridge MA USA

Center of Medical Genetics University of Antwerp and Antwerp University Hospital Antwerp Belgium

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est Centre Hospitalier Universitaire Dijon 21079 Dijon France

Chan Zuckerberg Biohub San Francisco CA USA

College of Applied Medical Sciences and Center for Genetics and Inherited Diseases Taibah University Madinah Kingdom of Saudi Arabia

Department of Anthropology University of Iceland Reykjavik Iceland

Department of Clinical Genetics Liverpool Hospital Sydney New South Wales Australia

Department of Genetics and Molecular Medicine Landspitali University Hospital Reykjavik Iceland

Department of Genetics Mid Atlantic Permanente Medical Group Washington DC USA

Department of Genetics UAB Heersink School of Medicine Birmingham AL USA

Department of Genome Sciences University of Washington School of Medicine Seattle WA USA

Department of Human Genetics Donders Institute Radboud University Medical Center Nijmegen The Netherlands

Department of Medical Genetics Center for Medical Genetics School of Basic Medical Sciences Peking University Beijing 100191 China

Department of Molecular Biology and Genetics Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Neurology Boston Children's Hospital Boston MA USA

Department of Neurology Harvard Medical School Boston MA USA

Department of Ophthalmology Boston Children's Hospital Boston MA USA

Department of Ophthalmology Harvard Medical School Boston MA USA

Department of Ophthalmology Landspitali University Hospital Reykjavik Iceland

Department of Pathology and Laboratory Medicine Genomic Medicine Center Children's Mercy Kansas City Kansas City MO USA

Department of Pediatrics Gemeinschaftsklinikum Mittelrhein Kemperhof Koblenzer Straße 115 155 56073 Koblenz Germany

Department of Pediatrics Johns Hopkins University School of Medicine Baltimore MD USA

Department of Pediatrics University of Nebraska Medical Center Omaha NE USA

Department of Physiology Faculty of Medicine University of Iceland

Department of Psychiatry and Behavioral Sciences University of Washington Seattle Washington USA

Departments of Pediatrics and Neurology University of Colorado School of Medicine and Children's Hospital Colorado Aurora CO USA

Division of Genetics Department of Pediatrics West Virginia School of Medicine Morgantown USA

eCODE Genetics Amgen Inc Reykjavik Iceland

F M Kirby Neurobiology Center Boston Children's Hospital Boston MA USA

Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland

GeneDx LLC Gaithersburg MD 20877 USA

Genetic Health Queensland Royal Brisbane and Women's Hospital Campus Herston Brisbane Australia

Howard Hughes Medical Institute Chevy Chase MD USA

Howard Hughes Medical Institute University of Washington Seattle WA USA

Human Genetics Department Radboud University Medical Center Nijmegen the Netherlands

Hunter Genetics Waratah New South Wales Australia

Independent Scientist

INGEMM Institute of Medical and Molecular Genetics IdiPAZ CIBERER Hospital Universitario La Paz Madrid Spain and ERNITHACA Madrid Spain

INSERM UMR1231 GAD team Univeristé de Bourgogne Europe Dijon France

Institute for Human Genetics and Genomic Medicine Medical Faculty RWTH Aachen University Aachen Germany

Institute of Human Genetics Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Institute of Molecular and Clinical Pathology and Medical Genetics University Hospital Ostrava Czech Republic

Institute of Physical Sciences University of Iceland Reykjavik Iceland

IRCCS Azienda Ospedaliero Universitaria di Bologna U O Genetica Medica 40138 Bologna Italy

Kennedy Krieger Institute Department of Neurology Baltimore Maryland USA

Leverhulme Centre for Demographic Science Nuffield Department of Population Health University of Oxford and Nuffield College Oxford UK

McKusick Nathans Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD USA

Medical Genetics Division Pediatric Department College of Medicine King Saud University Medical City King Saud University Riyadh Saudi Arabia

Munroe Meyer Institute for Genetics and Rehabilitation University of Nebraska Medical Center Omaha Nebraska USA

MVZ Institute for Clinical Genetics and Tumor Genetics Bonn Germany

Nantes Université CHU de Nantes CNRS INSERM l'institut du thorax F 44000 Nantes France

Nantes Université CHU de Nantes Service de Génétique médicale F 44000 Nantes France

Neuroscience Research Institute Peking University; Key Laboratory for Neuroscience Ministry of Education of China and National Health Commission of China Beijing 100191 China

Research Department King Khaled Eye Specialist Hospital Riyadh Saudi Arabia

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

School of Women's and Children's Health University of New South Wales Sydney New South Wales Australia

Service de Genetique Medicale Centre Labellisé Anomalies du Développement de l'Ouest CHU Rennes Rennes France

Service de Génétique Médicale Unité de Génétique Clinique Nantes France

Servicio de Genética Hospital Universitario de Toledo Toledo Spain

SSD Medical Genetics Maternal and Child Department AOU Policlinico Modena Modena Italy

T C Jenkins Department of Biophysics Johns Hopkins University Baltimore MD USA

The Genetics Institute Galilee Mefical Center Nahriya Israel

The Genetics Institute Rambam Health Care Campus Haifa Israel

The Louma G Laboratory of Epigenetic Research Faculty of Medicine University of Iceland Reykjavik Iceland

The University of Missouri Kansas City School of Medicine Kansas City MO USA

Victorian Clinical Genetics Services Murdoch Children's Research Institute Flemington Road Parkville Victoria Australia

Zobrazit více v PubMed

Pilarowski G. O. et al. Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet 55, 561–566 (2018). 10.1136/jmedgenet-2017-104759 PubMed DOI PMC

Loomes R., Hull L. & Mandy W. P. L. What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis. Journal of the American Academy of Child & Adolescent Psychiatry 56, 466–474 (2017). 10.1016/j.jaac.2017.03.013 PubMed DOI

Bölte S. et al. Sex and gender in neurodevelopmental conditions. Nat Rev Neurol 19, 136–159 (2023). 10.1038/s41582-023-00774-6 PubMed DOI PMC

Sunwoo Y., Seo S. H., Kim H.-J., Park M. S. & Cho A. Variant of CHD1 gene resulting in a Korean case of Pilarowski-Bjornsson syndrome. J Genet Med 19, 111–114 (2022). 10.5734/JGM.2022.19.2.111 DOI

Al-Aamri M., Alshaqaq M. & Al-Abdi S. Y. A Saudi Girl With Co-occurring CHD1 (Pilarowski-Bjornsson Syndrome) and ASH1L Gene Variants. Cureus 15, e49905 (2023). 10.7759/cureus.49905 PubMed DOI PMC

Stokes D. G., Tartof K. D. & Perry R. P. CHD1 is concentrated in interbands and puffed regions of Drosophila polytene chromosomes. Proceedings of the National Academy of Sciences 93, 7137–7142 (1996). 10.1073/pnas.93.14.7137 PubMed DOI PMC

Woodage T., Basrai M. A., Baxevanis A. D., Hieter P. & Collins F. S. Characterization of the CHD family of proteins. Proceedings of the National Academy of Sciences 94, 11472–11477 (1997). 10.1073/pnas.94.21.11472 PubMed DOI PMC

Tran H. G., Steger D. J., Iyer V. R. & Johnson A. D. The chromo domain protein Chd1p from budding yeast is an ATP-dependent chromatin-modifying factor. The EMBO Journal 19, 2323–2331 (2000). 10.1093/emboj/19.10.2323 PubMed DOI PMC

Lusser A., Urwin D. L. & Kadonaga J. T. Distinct activities of CHD1 and ACF in ATP-dependent chromatin assembly. Nature Structural & Molecular Biology 12, 160–166 (2005). 10.1038/nsmb884 PubMed DOI

Sims R. J. et al. Recognition of Trimethylated Histone H3 Lysine 4 Facilitates the Recruitment of Transcription Postinitiation Factors and Pre-mRNA Splicing. Molecular Cell 28, 665–676 (2007). 10.1016/j.molcel.2007.11.010 PubMed DOI PMC

Guzman-Ayala M. et al. Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast. Development 142, 118 (2015). 10.1242/dev.114843 PubMed DOI PMC

Simic R. et al. Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes. The EMBO Journal 22, 1846–1856 (2003). 10.1093/emboj/cdg179 PubMed DOI PMC

Skene P. J., Hernandez A. E., Groudine M. & Henikoff S. The nucleosomal barrier to promoter escape by RNA polymerase II is overcome by the chromatin remodeler Chd1. eLife 3, e02042 (2014). 10.7554/eLife.02042 PubMed DOI PMC

Biswas D. et al. A Role for Chd1 and Set2 in Negatively Regulating DNA Replication in Saccharomyces cerevisiae. Genetics 178, 649–659 (2008). 10.1534/genetics.107.084202 PubMed DOI PMC

Yadav T. & Whitehouse I. Replication-Coupled Nucleosome Assembly and Positioning by ATP-Dependent Chromatin-Remodeling Enzymes. Cell Reports 15, 715–723 (2016). 10.1016/j.celrep.2016.03.059 PubMed DOI PMC

Delamarre A. et al. MRX Increases Chromatin Accessibility at Stalled Replication Forks to Promote Nascent DNA Resection and Cohesin Loading. Molecular Cell 77, 395–410.e393 (2020). 10.1016/j.molcel.2019.10.029 PubMed DOI

Kari V. et al. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO reports 17, 1609–1623 (2016). 10.15252/embr.201642352 PubMed DOI PMC

Rüthemann P., Balbo Pogliano C., Codilupi T., Garajovà Z. & Naegeli H. Chromatin remodeler CHD1 promotes XPC to TFIIH handover of nucleosomal UV lesions in nucleotide excision repair. The EMBO Journal 36, 3372-3386-3386 (2017). 10.15252/embj.201695742 PubMed DOI PMC

Zhou J. et al. Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus. Nucleic Acids Research 46, 3891–3905 (2018). 10.1093/nar/gky128 PubMed DOI PMC

Shenoy T. et al. CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair. Annals of Oncology 28, 1495–1507 (2017). PubMed PMC

Bulut-Karslioglu A. et al. Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells. Nature Communications 12, 4859 (2021). 10.1038/s41467-021-25088-3 PubMed DOI PMC

Rechlin R. K., Splinter T. F. L., Hodges T. E., Albert A. Y. & Galea L. A. M. An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences. Nature Communications 13, 2137 (2022). 10.1038/s41467-022-29903-3 PubMed DOI PMC

McEwen B. S. & Milner T. A. Understanding the broad influence of sex hormones and sex differences in the brain. Journal of Neuroscience Research 95, 24–39 (2017). 10.1002/jnr.23809 PubMed DOI PMC

Augello M. A. et al. CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis. Cancer Cell 35, 603–617.e608 (2019). 10.1016/j.ccell.2019.03.001 PubMed DOI PMC

Metzger E. et al. Assembly of methylated KDM1A and CHD1 drives androgen receptor– dependent transcription and translocation. Nature Structural & Molecular Biology 23, 132–139 (2016). 10.1038/nsmb.3153 PubMed DOI

Sobreira N., Schiettecatte F., Valle D. & Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 36, 928–930 (2015). 10.1002/humu.22844 PubMed DOI PMC

Stessman H. A. F. et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature Genetics 49, 515–526 (2017). 10.1038/ng.3792 PubMed DOI PMC

Zhou X. et al. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nature Genetics 54, 1305–1319 (2022). 10.1038/s41588-022-01148-2 PubMed DOI PMC

Li S. et al. Identification of novel Mendelian disorders of the epigenetic machinery (MDEMs)-associated functional mutations and neurodevelopmental disorders. QJM: An International Journal of Medicine 116, 355–364 (2023). 10.1093/qjmed/hcad005 PubMed DOI

Karczewski K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). 10.1038/s41586-020-2308-7 PubMed DOI PMC

Cheng J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023). 10.1126/science.adg7492 PubMed DOI

Nodelman I. M. et al. Nucleosome recognition and DNA distortion by the Chd1 remodeler in a nucleotide-free state. Nature structural & molecular biology 29, 121–129 (2022). PubMed PMC

Piatti P. et al. Embryonic stem cell differentiation requires full length Chd1. Scientific Reports 5, 8007 (2015). 10.1038/srep08007 PubMed DOI PMC

Seibenhener M. L. & Wooten M. C. Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp, e52434 (2015). 10.3791/52434 PubMed DOI PMC

Vorhees C. V. & Williams M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature Protocols 1, 848–858 (2006). 10.1038/nprot.2006.116 PubMed DOI PMC

Caruso A., Ricceri L. & Scattoni M. L. Ultrasonic vocalizations as a fundamental tool for early and adult behavioral phenotyping of Autism Spectrum Disorder rodent models. Neuroscience & Biobehavioral Reviews 116, 31–43 (2020). 10.1016/j.neubiorev.2020.06.011 PubMed DOI

Groza T. et al. The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease. Nucleic Acids Research 51, D1038–D1045 (2023). 10.1093/nar/gkac972 PubMed DOI PMC

Salomoni P. & Calegari F. Cell cycle control of mammalian neural stem cells: putting a speed limit on G1. Trends in Cell Biology 20, 233–243 (2010). 10.1016/j.tcb.2010.01.006 PubMed DOI

Arletti R., Benelli A. & Bertolini A. Influence of oxytocin on feeding behavior in the rat. Peptides 10, 89–93 (1989). 10.1016/0196-9781(89)90082-X PubMed DOI

Noble E. E., Billington C. J., Kotz C. M. & Wang C. Oxytocin in the ventromedial hypothalamic nucleus reduces feeding and acutely increases energy expenditure. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 307, R737–R745 (2014). 10.1152/ajpregu.00118.2014 PubMed DOI PMC

Li E. et al. Control of lipolysis by a population of oxytocinergic sympathetic neurons. Nature 625, 175–180 (2024). 10.1038/s41586-023-06830-x PubMed DOI PMC

Peters S., Slattery D. A., Uschold-Schmidt N., Reber S. O. & Neumann I. D. Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 42, 225–236 (2014). 10.1016/j.psyneuen.2014.01.021 PubMed DOI

Grillon C. et al. Oxytocin increases anxiety to unpredictable threat. Mol Psychiatry 18, 958–960 (2013). 10.1038/mp.2012.156 PubMed DOI PMC

Winter J. et al. Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety. Molecular Psychiatry 28, 4742–4755 (2023). 10.1038/s41380-021-01141-x PubMed DOI PMC

Wei P.-C. et al. Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells. Cell 164, 644–655 (2016). 10.1016/j.cell.2015.12.039 PubMed DOI PMC

Rafnsdottir S. et al. SMYD5 is a regulator of the mild hypothermia response. Cell Reports 43 (2024). 10.1016/j.celrep.2024.114554 PubMed DOI PMC

Sondka Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Research 52, D1210–D1217 (2024). 10.1093/nar/gkad986 PubMed DOI PMC

Liang T. & Liao S. A very rapid effect of androgen on initiation of protein synthesis in prostate. Proceedings of the National Academy of Sciences 72, 706–709 (1975). 10.1073/pnas.72.2.706 PubMed DOI PMC

Ferrando A. A. et al. Testosterone injection stimulates net protein synthesis but not tissue amino acid transport. Am J Physiol 275, E864–871 (1998). 10.1152/ajpendo.1998.275.5.E864 PubMed DOI

Rizk J., Sahu R. & Duteil D. An overview on androgen-mediated actions in skeletal muscle and adipose tissue. Steroids 199, 109306 (2023). 10.1016/j.steroids.2023.109306 PubMed DOI

Handelsman D. J. Androgen physiology, pharmacology, use and misuse. Endotext [Internet] (2020).

Bycroft C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018). 10.1038/s41586-018-0579-z PubMed DOI PMC

Li S., Carss K. J., Halldorsson B. V., Cortes A. & Consortium U. B. W.-G. S. Whole-genome sequencing of half-a-million UK Biobank participants. medRxiv, 2023.2012.2006.23299426 (2023). 10.1101/2023.12.06.23299426 DOI

Bick A. G. et al. Genomic data in the All of Us Research Program. Nature 627, 340–346 (2024). 10.1038/s41586-023-06957-x PubMed DOI PMC

Granados A. et al. MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 175, 253–259 (2017). 10.1002/ajmg.c.31559 PubMed DOI PMC

Ostrer H. Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review. Sexual Development 16, 92–97 (2022). 10.1159/000522428 PubMed DOI

Kimura E. et al. MAP3K1 regulates female reproductive tract development. Disease Models & Mechanisms 17 (2024). 10.1242/dmm.050669 PubMed DOI PMC

Schoeler T. et al. Participation bias in the UK Biobank distorts genetic associations and downstream analyses. Nature Human Behaviour 7, 1216–1227 (2023). 10.1038/s41562-023-01579-9 PubMed DOI PMC

Benonisdottir S. & Kong A. Studying the genetics of participation using footprints left on the ascertained genotypes. Nature Genetics 55, 1413–1420 (2023). 10.1038/s41588-023-01439-2 PubMed DOI PMC

Bycroft C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018). 10.1038/s41586-018-0579-z PubMed DOI PMC

Rodríguez-Montes L. et al. Sex-biased gene expression across mammalian organ development and evolution. Science 382, eadf1046 (2023). 10.1126/science.adf1046 PubMed DOI PMC

Boukas L. et al. Coexpression patterns define epigenetic regulators associated with neurological dysfunction. Genome Research 29, 532–542 (2019). 10.1101/gr.239442.118 PubMed DOI PMC

Ascano M. Jr. et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492, 382–386 (2012). 10.1038/nature11737 PubMed DOI PMC

McAninch D. S. et al. Fragile X mental retardation protein recognizes a G quadruplex structure within the survival motor neuron domain containing 1 mRNA 5′-UTR. Molecular BioSystems 13, 1448–1457 (2017). 10.1039/C7MB00070G PubMed DOI PMC

Banerjee-Basu S. & Packer A. SFARI Gene: an evolving database for the autism research community. Disease Models & Mechanisms 3, 133–135 (2010). 10.1242/dmm.005439 PubMed DOI

Gonçalves S. et al. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. PLOS Genetics 14, e1007386 (2018). 10.1371/journal.pgen.1007386 PubMed DOI PMC

Stephenson S. E. M. et al. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. The American Journal of Human Genetics 109, 601–617 (2022). 10.1016/j.ajhg.2022.03.002 PubMed DOI PMC

Riestra M. R. et al. Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome. Journal of Clinical Immunology 44, 2 (2023). 10.1007/s10875-023-01627-z PubMed DOI PMC

Xu C. et al. Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: Evidence of gene×gender interaction. Journal of Affective Disorders 145, 95–99 (2013). 10.1016/j.jad.2012.07.017 PubMed DOI

Schoberleitner I. et al. Role for Chromatin Remodeling Factor Chd1 in Learning and Memory. Frontiers in Molecular Neuroscience 12 (2019). 10.3389/fnmol.2019.00003 PubMed DOI PMC

Sofer Y. et al. Sexually dimorphic oxytocin circuits drive intragroup social conflict and aggression in wild house mice. Nature Neuroscience 27, 1565–1573 (2024). 10.1038/s41593-024-01685-5 PubMed DOI

Uhl-Bronner S., Waltisperger E., Martínez-Lorenzana G., Condes Lara M. & Freund-Mercier M. J. Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat. Neuroscience 135, 147–154 (2005). 10.1016/j.neuroscience.2005.05.025 PubMed DOI

Sarn N., Thacker S., Lee H. & Eng C. Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity. Molecular Autism 12, 41 (2021). 10.1186/s13229-021-00448-4 PubMed DOI PMC

Spritzer M. D. & Galea L. A. Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats. Developmental neurobiology 67, 1321–1333 (2007). PubMed

Hamson D. K. et al. Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats. Endocrinology 154, 3294–3304 (2013). PubMed

La Rosa P. et al. Androgen Receptor signaling promotes the neural progenitor cell pool in the developing cortex. Journal of Neurochemistry 157, 1153–1166 (2021). 10.1111/jnc.15192 PubMed DOI

Kelava I., Chiaradia I., Pellegrini L., Kalinka A. T. & Lancaster M. A. Androgens increase excitatory neurogenic potential in human brain organoids. Nature 602, 112–116 (2022). 10.1038/s41586-021-04330-4 PubMed DOI PMC

Nuñez J. L., Jurgens H. A. & Juraska J. M. Androgens reduce cell death in the developing rat visual cortex. Developmental Brain Research 125, 83–88 (2000). 10.1016/S0165-3806(00)00126-7 PubMed DOI

Tetzlaff J. E., Huppenbauer C. B., Tanzer L., Alexander T. D. & Jones K. J. Motoneuron injury and repair. Journal of Molecular Neuroscience 28, 53–64 (2006). 10.1385/JMN:28:1:53 PubMed DOI

Pihlajamaa P. et al. Tissue-specific pioneer factors associate with androgen receptor cistromes and transcription programs. The EMBO Journal 33, 312-326-326 (2014). 10.1002/embj.201385895 PubMed DOI PMC

Haffner M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature Genetics 42, 668–675 (2010). 10.1038/ng.613 PubMed DOI PMC

Feng W. et al. Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme. Nature Communications 8, 14758 (2017). 10.1038/ncomms14758 PubMed DOI PMC

Gonçalves C. I. et al. High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism. Sci Rep 9, 1597 (2019). 10.1038/s41598-018-38178-y PubMed DOI PMC

Zhou Q., Sheng W., Yang S. & Zou C. The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism. Journal of Oncology 2022, 7973726 (2022). 10.1155/2022/7973726 PubMed DOI PMC

Tartaglia M. et al. Paternal Germline Origin and Sex-Ratio Distortion in Transmission of PTPN11 Mutations in Noonan Syndrome. The American Journal of Human Genetics 75, 492–497 (2004). 10.1086/423493 PubMed DOI PMC

Leroy C. et al. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients. Eur J Hum Genet 21, 602–612 (2013). 10.1038/ejhg.2012.230 PubMed DOI PMC

Ong-Pålsson E. et al. The β-Secretase Substrate Seizure 6–Like Protein (SEZ6L) Controls Motor Functions in Mice. Molecular Neurobiology 59, 1183–1198 (2022). 10.1007/s12035-021-02660-y PubMed DOI PMC

O’Tuathaigh C. M. et al. Sexually dimorphic changes in the exploratory and habituation profiles of heterozygous neuregulin-1 knockout mice. NeuroReport 17 (2006). PubMed

Taylor S. B., Markham J. A., Taylor A. R., Kanaskie B. Z. & Koenig J. I. Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats.Behavioural Brain Research 224, 223–232 (2011). 10.1016/j.bbr.2011.05.008 PubMed DOI PMC

Zhang Z. et al. Sex differences in circulating neuregulin1-β1 and β-secretase 1 expression in childhood-onset schizophrenia. Comprehensive Psychiatry 100, 152176 (2020). 10.1016/j.comppsych.2020.152176 PubMed DOI

Ananloo E. S., Yoosefee S. & Karimipour M. Neuregulin1 gene variants as a biomarker for cognitive impairments in patients with schizophrenia. European Journal of Psychiatry 34, 11–19 (2020). 10.1016/j.ejpsy.2019.12.004 DOI

McNairn A. J., Chuang C. H., Bloom J. C., Wallace M. D. & Schimenti J. C. Female-biased embryonic death from inflammation induced by genomic instability. Nature 567, 105–108 (2019). 10.1038/s41586-019-0936-6 PubMed DOI PMC

Rodrigues E. D. S. et al. Variant-level matching for diagnosis and discovery: Challenges and opportunities. Hum Mutat 43, 782–790 (2022). 10.1002/humu.24359 PubMed DOI PMC

Hunter J. D. Matplotlib: A 2D Graphics Environment. Computing in Science & Engineering 9, 90–95 (2007). 10.1109/MCSE.2007.55 DOI

Pfafl M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29, e45 (2001). 10.1093/nar/29.9.e45 PubMed DOI PMC

Durkin M. E., Qian X., Popescu N. C. & Lowy D. R. Isolation of Mouse Embryo Fibroblasts. Bio Protoc 3 (2013). 10.21769/bioprotoc.908 PubMed DOI PMC

Towbin H., Staehelin T. & Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proceedings of the National Academy of Sciences 76, 4350–4354 (1979). 10.1073/pnas.76.9.4350 PubMed DOI PMC

Schindelin J. et al. Fiji: an open-source platform for biological-image analysis. Nature Methods 9, 676–682 (2012). 10.1038/nmeth.2019 PubMed DOI PMC

Feather-Schussler D. N. & Ferguson T. S. A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy. J Vis Exp (2016). 10.3791/53569 PubMed DOI PMC

Bjornsson H. T. et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci Transl Med 6, 256ra135 (2014). 10.1126/scitranslmed.3009278 PubMed DOI PMC

García-Llorca A., Ólafsson K. H., Sigurdsson A. T. & Eysteinsson T. Progressive Cone-Rod Dystrophy and RPE Dysfunction in Mitfmi/+ Mice. Genes 14, 1458 (2023). PubMed PMC

Elizarraras J. M. et al. WebGestalt 2024: faster gene set analysis and new support for metabolomics and multi-omics. Nucleic Acids Research 52, W415–W421 (2024). 10.1093/nar/gkae456 PubMed DOI PMC

BD V. d. A. G. O. C. Genomics in the Cloud: Using Docker, GATK, and WDL in Terra (1st edition). (O’Reilly Media, 2020).

Dobin A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013). 10.1093/bioinformatics/bts635 PubMed DOI PMC

Danecek P. et al. Twelve years of SAMtools and BCFtools. GigaScience 10, giab008 (2021). 10.1093/gigascience/giab008 PubMed DOI PMC

Manders F. et al. MutationalPatterns: the one stop shop for the analysis of mutational processes. BMC Genomics 23, 134 (2022). 10.1186/s12864-022-08357-3 PubMed DOI PMC