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

6533b86efe1ef96bd12cac1a

RESEARCH PRODUCT

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

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

subject

Male Developmental Disabilities Intellectual disability cholesterol pathway Whole Exome Sequencing chemistry.chemical_compound Missense mutation Age of Onset Child Intramolecular Transferases Genetics (clinical)Exome sequencing Genetics Sanger sequencing 0303 health sciences biology Lanosterol 030305 genetics & heredity LSS 3. Good health Pedigree Cholesterol Phenotype intellectual disability Child Preschool Allelic Imbalance Congenital cataracts symbols Female Squalene early-onset epileptic encephalopathy 03 medical and health sciences symbols.namesake Lanosterol Cholesterol pathway Exome Sequencing medicine Humans 030304 developmental biology Epilepsy Infant Alopecia alopecia medicine.disease Early-onset epileptic encephalopathy chemistry Mutation biology.protein Hypotrichosis [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology Lanosterol synthase

description

International audience; 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.

year	journal	country	edition	language
2019-01-01

10.1038/s41436-019-0445-x https://hdl.handle.net/2078.1/239317