Further characterisation of ARX -related disorders in females due to inherited or de novo variants

Mathilde Gras; Solveig Heide; Boris Keren; Stéphanie Valence; Catherine Garel; Sandra Whalen; Anna C Jansen; Kathelijn Keymolen; Katrien Stouffs; Mélanie Jennesson; Céline Poirsier; Gaetan Lesca; Christel Depienne; Caroline Nava; Agnès Rastetter; Aurore Curie; Laurence Cuisset; Vincent Des Portes; Mathieu Milh; Perrine Charles; Cyril Mignot; Delphine Héron

doi:10.1136/jmg-2023-109203

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Further characterisation of ARX -related disorders in females due to inherited or de novo variants

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Further characterisation of ARX -related disorders in females due to inherited or de novo variants

Mathilde Gras, Solveig Heide, Boris Keren, Stéphanie Valence, Catherine Garel, Sandra Whalen, Anna C Jansen, Kathelijn Keymolen, Katrien Stouffs, Mélanie Jennesson, …

Journal of medical genetics, Vol.61(2), pp.103-108

01/02/2024

DOI: https://doi.org/10.1136/jmg-2023-109203

PMID: 37879892

Résumé

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 In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited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.

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Titre: Further characterisation of ARX -related disorders in females due to inherited or de novo variants
Créateurs - sans rôle: Mathilde Gras - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France
Solveig Heide - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France, Reference Center for Rare Diseases « Intellectual disabilities of rare causes » Déficiences Intellectuelles de Causes Rares, University Hospital Pitié Salpêtrière, Paris, France, Doctoral College, Sorbonne University, Paris, France
Boris Keren - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France
Stéphanie Valence - Unit of Pediatric Neurology, APHP Sorbonne Université, Armand-Trousseau Hospital, Paris, France, Reference Center for Rare Diseases « Intellectual disabilites of rare causes » Déficiences Intellectuelles de Causes Rares, Armand-Trousseau Hospital, Paris, France
Catherine Garel - Unit of Pediatric Radiology, APHP Sorbonne Université, Armand-Trousseau Hospital, Paris, France
Sandra Whalen - Hôpital Armand-Trousseau
Anna C Jansen - Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium
Kathelijn Keymolen - Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussels), Vrije Universiteit Brussel (VUB), Brussels, Belgium
Katrien Stouffs - Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussels), Vrije Universiteit Brussel (VUB), Brussels, Belgium
Mélanie Jennesson - Pediatrics Unit, University Hospital of Reims, American Memorial Hospital, Reims, France
Céline Poirsier - UF génétique clinique, Pôle Femme-Parents-Enfants, CHU Reims, Reims, France
Gaetan Lesca - Department of Genetics, Referral Center for Developmental Anomalies and Malformative Syndromes, Centre-est HCL, Hospices Civils de Lyon, Lyon, France
Christel Depienne - University of Duisburg-Essen
Caroline Nava - Brain Institute, Paris, France
Agnès Rastetter - Brain Institute, Paris, France
Aurore Curie - Reference Centre for Rare Diseases « Intellectual disabilities of rare causes », Civil Hospices of Lyon, Lyon, France, University Lyon 1 Faculty of Medicine Lyon-Est, Lyon, France
Laurence Cuisset - Université Paris Cité
Vincent Des Portes - Reference Centre for Rare Diseases « Intellectual disabilities of rare causes », Civil Hospices of Lyon, Lyon, France, University Lyon 1 Faculty of Medicine Lyon-Est, Lyon, France
Mathieu Milh - Hôpital de la Timone
Perrine Charles - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France, Reference Center for Rare Diseases « Intellectual disabilities of rare causes » Déficiences Intellectuelles de Causes Rares, University Hospital Pitié Salpêtrière, Paris, France
Cyril Mignot - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France, Reference Center for Rare Diseases « Intellectual disabilities of rare causes » Déficiences Intellectuelles de Causes Rares, University Hospital Pitié Salpêtrière, Paris, France
Delphine Héron - Department of Clinical Genetics, APHP Sorbonne Université, University Hospital Pitié Salpêtrière, Paris, France, Reference Center for Rare Diseases « Intellectual disabilities of rare causes » Déficiences Intellectuelles de Causes Rares, University Hospital Pitié Salpêtrière, Paris, France
Détails de publication: Journal of medical genetics, Vol.61(2), pp.103-108
Nombre de pages: 6
Identifiants: 99149284609311
Unité académique: BioCampus Montpellier - BCM
Langue: English
Type de ressource: Journal article