Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.
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.
['Besnard|Thomas|T|', 'Sloboda|Natacha|N|', 'Goldenberg|Alice|A|', 'Küry|Sébastien|S|', 'Cogné|Benjamin|B|', 'Breheret|Flora|F|', 'Trochu|Eva|E|', 'Conrad|Solène|S|', 'Vincent|Marie|M|', 'Deb|Wallid|W|', 'Balguerie|Xavier|X|', 'Barbarot|Sébastien|S|', 'Baujat|Geneviève|G|', 'Ben-Omran|Tawfeg|T|', 'Bursztejn|Anne-Claire|AC|', 'Carmignac|Virginie|V|', 'Datta|Alexandre N|AN|', 'Delignières|Aline|A|', 'Faivre|Laurence|L|', 'Gardie|Betty|B|', 'Guéant|Jean-Louis|JL|', 'Kuentz|Paul|P|', 'Lenglet|Marion|M|', 'Nassogne|Marie-Cécile|MC|', 'Ramaekers|Vincent|V|', 'Schnur|Rhonda E|RE|', 'Si|Yue|Y|', 'Torti|Erin|E|', 'Thevenon|Julien|J|', 'Vabres|Pierre|P|', 'Van Maldergem|Lionel|L|', 'Wand|Dorothea|D|', 'Wiedemann|Arnaud|A|', 'Cariou|Bertrand|B|', 'Redon|Richard|R|', 'Lamazière|Antonin|A|', 'Bézieau|Stéphane|S|', 'Feillet|Francois|F|', 'Isidor|Bertrand|B|']
D017668:Age of Onset D000505:Alopecia D002648:Child D002675:Child, Preschool D002784:Cholesterol D002658:Developmental Disabilities D004827:Epilepsy D005260:Female D006801:Humans D007223:Infant D008607:Intellectual Disability D019751:Intramolecular Transferases D007810:Lanosterol D008297:Male D009154:Mutation D010375:Pedigree D010641:Phenotype D013185:Squalene D000073359:Whole Exome Sequencing
LSS alopecia intellectual disability cholesterol pathway early-onset epileptic encephalopathy