DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations.

Autor:	Lavillaureix A; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France., Rollier P; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France., Kim A; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA., Panasenkava V; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France., De Tayrac M; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France; Génétique Moléculaire et Génomique, FHU GenOMedS, CHU de Rennes, Rennes, France., Carré W; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France; Génétique Moléculaire et Génomique, FHU GenOMedS, CHU de Rennes, Rennes, France., Guyodo H; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France., Faoucher M; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France; Génétique Moléculaire et Génomique, FHU GenOMedS, CHU de Rennes, Rennes, France., Poirel E; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France., Akloul L; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France., Quélin C; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France., Whalen S; APHP, Sorbonne Université, Département de Génétique, Centre de Référence Maladies Rares des Anomalies du Développement et Syndromes Malformatifs, Hôpital Trousseau & Groupe Hospitalier Pitié-Salpêtrière, Paris, France., Bos J; Department of Human Genetics, Section Clinical Genetic, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Broekema M; Department of Human Genetics, Section Clinical Genetic, Amsterdam University Medical Centers, Amsterdam, The Netherlands., van Hagen JM; Department of Human Genetics, Section Clinical Genetic, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Grand K; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA., Allen-Sharpley M; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA., Magness E; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX., McLean SD; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Division of Clinical Genetics, Christus Children's, San Antonio, TX., Kayserili H; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey., Altunoglu U; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey., En Qi Chong A; Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Xue S; Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Jeanne M; Service de Génétique, FHU GenOMedS, CHRU de Tours, Tours, France; UMR1253, iBrain, Inserm, University of Tours, Tours, France., Almontashiri N; Center for Genetics and Inherited Diseases (CGID), Taibah University, Madinah, Saudi Arabia., Habhab W; Department of Genetic Medicine, Faculty of Medicine, Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia., Vanlerberghe C; CHU Lille, Clinique de Génétique Guy Fontaine, Lille, France., Faivre L; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Centre Hospitalier Universitaire, Dijon, France; Genetics of Developmental Disorders, INSERM UMR1231, Université de Bourgogne, Dijon, France., Viora-Dupont E; Genetics of Developmental Disorders, INSERM UMR1231, Université de Bourgogne, Dijon, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Centre Hospitalier Universitaire, Dijon, France., Philippe C; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Centre Hospitalier Universitaire, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon, Dijon, France., Safraou H; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, Centre Hospitalier Universitaire, Dijon, France; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon, Dijon, France., Laffargue F; CHU Clermont Ferrand, Service de Génétique Clinique, Clermont Ferrand, France., Mittendorf L; Department for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany., Abou Jamra R; Institute of Human Genetics, Leipzig, Germany., Patil SJ; Division of Genetics, Narayana Hrudayalaya Hospitals/Mazumdar Shaw Medical Centre, Bangalore, India., Dalal A; Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India., Sarma AS; Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India., Keren B; APHP, Sorbonne Université, Département de Génétique Médicale, GH Pitié Salpêtrière, Paris, France., Reversade B; Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A∗STAR, Department of Physiology, Cardiovascular Disease, Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey; Laboratory of Human Genetics and Therapeutics Smart-Health Initiative, BESE, KAUST, Thuwal, Kingdom of Saudi Arabia., Dubourg C; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France; Génétique Moléculaire et Génomique, FHU GenOMedS, CHU de Rennes, Rennes, France., Odent S; Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France., Dupé V; Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Rennes, France. Electronic address: valerie.dupe@univ-rennes.fr.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Jul; Vol. 26 (7), pp. 101126. Date of Electronic Publication: 2024 Mar 24.
DOI:	10.1016/j.gim.2024.101126
Abstrakt:	Purpose: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants. Methods: This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. Results: A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance). Conclusion: The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant. Competing Interests: Conflict of Interest All authors declare no conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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