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Further characterisation of ARX-related disorders in females due to inherited or de novo variants
  1. Mathilde Gras1,
  2. Solveig Heide1,2,3,
  3. Boris Keren1,
  4. Stéphanie Valence4,5,
  5. Catherine Garel6,
  6. Sandra Whalen7,
  7. Anna C Jansen8,
  8. Kathelijn Keymolen9,
  9. Katrien Stouffs9,
  10. Mélanie Jennesson10,
  11. Céline Poirsier11,
  12. Gaetan Lesca12,
  13. Christel Depienne13,
  14. Caroline Nava14,
  15. Agnès Rastetter14,
  16. Aurore Curie15,16,
  17. Laurence Cuisset17,
  18. Vincent Des Portes15,16,
  19. Mathieu Milh18,
  20. Perrine Charles1,2,
  21. Cyril Mignot1,2,
  22. Delphine Héron1,2
  1. 1 Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France
  2. 2 Reference Center for Rare Diseases « Intellectual disabilities of rare causes » Déficiences Intellectuelles de Causes Rares, University Hospital Pitié Salpêtrière, Paris, France
  3. 3 Doctoral College, Sorbonne University, Paris, France
  4. 4 Unit of Pediatric Neurology, APHP Sorbonne Université, Armand-Trousseau Hospital, Paris, France
  5. 5 Reference Center for Rare Diseases « Intellectual disabilites of rare causes » Déficiences Intellectuelles de Causes Rares, Armand-Trousseau Hospital, Paris, France
  6. 6 Unit of Pediatric Radiology, APHP Sorbonne Université, Armand-Trousseau Hospital, Paris, France
  7. 7 Department of Clinical Genetics and Reference Center for Rare Diseases « Developmental disorders and syndromes », APHP Sorbonne Université, Armand-Trousseau Hospital, Paris, France
  8. 8 Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium
  9. 9 Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussels), Vrije Universiteit Brussel (VUB), Brussels, Belgium
  10. 10 Pediatrics Unit, University Hospital of Reims, American Memorial Hospital, Reims, France
  11. 11 UF génétique clinique, Pôle Femme-Parents-Enfants, CHU Reims, Reims, France
  12. 12 Department of Genetics, Referral Center for Developmental Anomalies and Malformative Syndromes, Centre-est HCL, Hospices Civils de Lyon, Lyon, France
  13. 13 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
  14. 14 Brain Institute, Paris, France
  15. 15 Reference Centre for Rare Diseases « Intellectual disabilities of rare causes », Civil Hospices of Lyon, Lyon, France
  16. 16 University Lyon 1 Faculty of Medicine Lyon-Est, Lyon, France
  17. 17 APHP Centre Université Paris Cité, Service de Médecine Génomique des Maladies de Système et d’Organe, Cochin Hospital, Paris, France
  18. 18 Department of Neurology Pediatrics, AP-HM, Hôpital de la Timone, Marseille, France
  1. Correspondence to Mrs Mathilde Gras, Department of Clinical Genetics, University Hospital Pitié Salpêtrière, Paris 75013, France; mathilde.gras{at}


The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.

  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities
  • Epilepsy
  • Genetic Counseling
  • Heredity
  • Human Genetics

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  • MG and SH contributed equally.

  • Contributors DH is at the origin of this project. She initiated and supervised the project with the help of CM. SH and MG carried out the literature review, data collection and data analysis. These two authors contributed equally to the work and are both first authors. The other coauthors contributed by providing clinical information of the patients or analysing the genetic data, and reviewed the article with comments and modifications to improve it.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.