Saad M. Al Shareef, Sulman Basit, Sha Li, Corinne Pfister, Sylvain Pradervand, Michel Lecendreux, Geert Mayer, Yves Dauvilliers, Vincenzo Salpietro, Henry Houlden, Ahmed S. BaHammam, Mehdi Tafti
Kleine-Levin syndrome (KLS) is a rare periodic hypersomnia with associated beha- vioural abnormalities but with often favourable prognosis. There is excess risk of KLS in first-degree relatives, suggesting a strong genetic contribution. So far, no mutation is identified in KLS and comprehensive genetic analysis of affected individ- uals is lacking. Here we performed whole genome single-nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected mem- bers. The identified gene with a mutation was resequenced in 38 sporadic KLS patients and the expression of the gene product was mapped in the mouse brain. Linkage analysis mapped the disease locus to chromosome 3 and exome analysis identified a heterozygous missense variant in LMOD3 (p.E142D) in the linkage inter- val. The variant was found to segregate in all affected and one presumably unaf- fected member of the family. Resequencing LMOD3 in 38 other KLS patients and their families revealed three other low frequency or rare missense variants in seven cases that were inherited with incomplete penetrance. LMOD3 is expressed in the brain and colocalized with major structures involved in the regulation of vigilance states. LMOD proteins are structural proteins and seem to be developmentally regu- lated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease