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Kleine‐Levin syndrome is associated with LMOD3 variants
Author(s) -
Al Shareef Saad M.,
Basit Sulman,
Li Sha,
Pfister Corinne,
Pradervand Sylvain,
Lecendreux Michel,
Mayer Geert,
Dauvilliers Yves,
Salpietro Vincenzo,
Houlden Henry,
BaHammam Ahmed S.,
Tafti Mehdi
Publication year - 2019
Publication title -
journal of sleep research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.297
H-Index - 117
eISSN - 1365-2869
pISSN - 0962-1105
DOI - 10.1111/jsr.12718
Subject(s) - missense mutation , genetics , exome sequencing , locus (genetics) , biology , exome , penetrance , single nucleotide polymorphism , genetic linkage , snp , gene , mutation , genotype , phenotype
Kleine‐Levin syndrome (KLS) is a rare periodic hypersomnia with associated behavioural 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 individuals is lacking. Here we performed whole genome single‐nucleotide polymorphism (SNP) genotyping and exome sequencing in a large family with seven affected members. 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 interval. The variant was found to segregate in all affected and one presumably unaffected 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 regulated. Our findings suggest that KLS might be a structural/neurodevelopmental brain disease.