Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome PMID: 30723320

Target-related Cytokines

2026-09-23

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

Genet Med. 2019 Sep;21(9):2025-2035. doi: 10.1038/s41436-019-0445-x.

Thomas Besnard ¹ ² , Natacha Sloboda ³ , Alice Goldenberg ⁴ , Sébastien Küry ⁵ ⁶ , Benjamin Cogné ⁵ ⁶ , Flora Breheret ⁵ , Eva Trochu ⁵ , Solène Conrad ⁵ , Marie Vincent ⁵ ⁶ , Wallid Deb ⁵ ⁶ , Xavier Balguerie ⁷ , Sébastien Barbarot ⁸ , Geneviève Baujat ⁹ , Tawfeg Ben-Omran ¹⁰ , Anne-Claire Bursztejn ¹¹ , Virginie Carmignac ¹² ¹³ , Alexandre N Datta ¹⁴ , Aline Delignières ¹⁵ , Laurence Faivre ¹² ¹³ , Betty Gardie ⁶ ¹⁶ , Jean-Louis Guéant ³ , Paul Kuentz ¹² ¹³ , Marion Lenglet ⁶ ¹⁶ , Marie-Cécile Nassogne ¹⁷ , Vincent Ramaekers ¹⁸ , Rhonda E Schnur ¹⁹ , Yue Si ¹⁹ , Erin Torti ¹⁹ , Julien Thevenon ²⁰ , Pierre Vabres ¹² ¹³ , Lionel Van Maldergem ²¹ ²² , Dorothea Wand ²³ , Arnaud Wiedemann ³ , Bertrand Cariou ⁶ , Richard Redon ⁶ , Antonin Lamazière ²⁴ , Stéphane Bézieau ⁵ ⁶ , Francois Feillet ³ , Bertrand Isidor ²⁵ ²⁶

Affiliations

1. CHU de Nantes, Service de Génétique Médicale, Nantes, France. [email protected].
2. L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Nantes, France. [email protected].
3. 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), Nancy, France.
4. Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
5. CHU de Nantes, Service de Génétique Médicale, Nantes, France.
6. L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Nantes, France.
7. Department of Dermatology, University Hospital Center of Rouen, Rouen, France.
8. CHU de Nantes, Department of Dermatology, Nantes, France.
9. Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.
10. Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
11. Dermatology department, hôpital Brabois, Vandœuvre-Lès, Vandœuvre-lès-Nancy, France.
12. Centre de Genetique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, Dijon, France.
13. UMR-Inserm 1231 GAD Team, Genetique des Anomalies du Développement, Université de Bourgogne Franche-Comte, Dijon, France.
14. Department of Pediatric Neurology and Developmental Medicine, University of Basel Children's Hospital (UKBB), Basel, Switzerland.
15. CH Auray-Vannes, Hôpital Bretagne Atlantique, Service de Pediatrie, Vannes, France.
16. Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France.
17. Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium.
18. Center of Autism and Department of Genetics, University Hospital Liege (CHU), Liège, Belgium.
19. GeneDx, 207 Perry Parkway, Gaithersburg, MD, USA.
20. Centre de Génétique, Hôpital Couple-Enfant, CHU de Grenoble-Alpes, La Tronche, France.
21. Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
22. Integrative and Cognitive Neurosciences Research Unit EA481, University of Franche-Comté, Besançon, France.
23. Department Medical Genetic and Pathology, University Hospital of Basel (USB), Basel, Switzerland.
24. Laboratory of Mass Spectrometry, INSERM ERL 1157, CNRS UMR 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine, Paris, France.
25. CHU de Nantes, Service de Génétique Médicale, Nantes, France. [email protected].
26. L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Nantes, France. [email protected].

Abstract

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.

Keywords

LSS; alopecia; cholesterol pathway; early-onset epileptic encephalopathy; intellectual disability.