Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

Thomas Besnard; Natacha Sloboda; Alice Goldenberg; Sébastien Küry; Benjamin Cogné; Flora Breheret; Eva Trochu; Solène Conrad; Marie Vincent; Wallid Deb; Xavier Balguerie; Sébastien Barbarot; Geneviève Baujat; Tawfeg Ben-Omran; Anne-Claire Bursztejn; Virginie Carmignac; Alexandre N. Datta; Aline Delignières; Laurence Faivre; Betty Gardie; Jean-Louis Guéant; Paul Kuentz; Marion Lenglet; Marie-Cécile Nassogne; Vincent Ramaekers; Rhonda E. Schnur; Yue Si; Erin Torti; Julien Thevenon; Pierre Vabres; Lionel Van Maldergem; Dorothea Wand; Arnaud Wiedemann; Bertrand Cariou; Richard Redon; Antonin Lamazière; Stéphane Bézieau; Francois Feillet; Bertrand Isidor

doi:10.1038/s41436-019-0445-x

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Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

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Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome

Thomas Besnard, Natacha Sloboda, Alice Goldenberg, Sébastien Küry, Benjamin Cogné, Flora Breheret, Eva Trochu, Solène Conrad, Marie Vincent, Wallid Deb, …

Genetics in medicine, Vol.21(9), pp.2025-2035

01/09/2019

DOI: https://doi.org/10.1038/s41436-019-0445-x

PMID: 30723320

Résumé

Article

Biomedical and Life Sciences

Biomedicine

Général

Human Genetics

Laboratory Medicine

Purpose Lanosterol synthase ( LSS ) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. Methods Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. Results We reported ten APMR individuals from six unrelated families with biallelic variants in LSS . We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. Conclusion In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

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Titre: Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome
Créateurs - sans rôle: Thomas Besnard - Nantes Université
Natacha Sloboda - INSERM, UMR 1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Alice Goldenberg - Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine
Sébastien Küry - Nantes Université
Benjamin Cogné - Nantes Université
Flora Breheret - CHU de Nantes, Service de Génétique Médicale
Eva Trochu - CHU de Nantes, Service de Génétique Médicale
Solène Conrad - Centre Hospitalier Universitaire de Nantes
Marie Vincent - Nantes Université
Wallid Deb - Nantes Université
Xavier Balguerie - Department of Dermatology, University Hospital Center of Rouen
Sébastien Barbarot - CHU de Nantes, Department of Dermatology
Geneviève Baujat - Sorbonne Paris Cité
Tawfeg Ben-Omran - Hamad Medical Corporation
Anne-Claire Bursztejn - Dermatology department, hôpital Brabois
Virginie Carmignac - Université de Bourgogne
Alexandre N. Datta - Department of Pediatric Neurology and Developmental Medicine, University of Basel Children’s Hospital (UKBB)
Aline Delignières - CH Auray-Vannes, Hôpital Bretagne Atlantique, Service de Pediatrie
Laurence Faivre - Centre de Genetique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs de l’Est, FHU-TRANSLAD, CHU Dijon, UMR-Inserm 1231 GAD Team, Genetique des Anomalies du Développement, Université de Bourgogne Franche-Comte
Betty Gardie - Université Paris Sciences et Lettres
Jean-Louis Guéant - INSERM, UMR 1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Paul Kuentz - Université de Bourgogne
Marion Lenglet - L’institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Ecole Pratique des Hautes Etudes, PSL Research University
Marie-Cécile Nassogne - Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain
Vincent Ramaekers - Center of Autism and Department of Genetics, University Hospital Liege (CHU)
Rhonda E. Schnur - GeneDx, 207 Perry Parkway
Yue Si - GeneDx, 207 Perry Parkway
Erin Torti - GeneDx, 207 Perry Parkway
Julien Thevenon - Hôpital Couple Enfant
Pierre Vabres - Université de Bourgogne
Lionel Van Maldergem - Centre de génétique humaine, Université de Franche-Comté, Integrative and Cognitive Neurosciences Research Unit EA481, University of Franche-Comté
Dorothea Wand - Department Medical Genetic and Pathology, University Hospital of Basel (USB)
Arnaud Wiedemann - INSERM, UMR 1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Bertrand Cariou - Nantes Université
Richard Redon - L’institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes
Antonin Lamazière - Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine
Stéphane Bézieau - Nantes Université
Francois Feillet - INSERM, UMR 1256 Nutrition-Genetics-Environmental Risk Exposure and Reference Centre of Inborn Metabolism Diseases, University of Lorraine and University Hospital Centre of Nancy (CHRU Nancy)
Bertrand Isidor - Nantes Université
Détails de publication: Genetics in medicine, Vol.21(9), pp.2025-2035
Éditeur: Nature Publishing Group US
Nombre de pages: 11
Identifiants: 99158905809311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article