Kleine‐Levin syndrome is associated with LMOD3 variants

Abstract

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.

Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

“…We observed no significant differences in mutational burden in LMOD3 gene between cases and controls (p=0.13; see Dataset S13B ). Variant level analyses in KLS probands and sporadic cases (n=17) revealed a previously reported single site rs35740823 (chr3:69171290; p.R83H) to be enriched in KLS cases (allelic OR=3.8; p=0.06) as compared to controls (60) (see Dataset S13B ). We therefore imputed this LMOD3 variant rs35740823 and analyzed for associations in 151 KLS cases and 478 controls derived from replication cohort and predominantly of European origin but did not find any remarkable differences (OR=1.1; p=0.77; Dataset S13B ).…”

“…Following up on a recent study suggesting increased mutation load in the LMOD3 gene in familial KLS cases (60), we analyzed the LMOD3 burden in our cohort of KLS probands and sporadic cases (n=17) compared to controls (n=286). We observed no significant differences in mutational burden in LMOD3 gene between cases and controls (p=0.13; see Dataset S13B ).…”

“…For example, a 20-year-old study had suggested an HLA-DQ2 association (12) in KLS, but this was not confirmed either in other studies (3, 8, 13) nor in our current analyses. A recent study (60) focused on a large Saudi pedigree KLS affected family where a rs111848977 p.E142D mutation in LMOD3 was observed to cosegregate. This study also reported an increased burden of damaging mutations, including p.R23H in LMOD3 in KLS, a gene involved in nemaline myopathy 10 (62).…”

Compound Heterozygosity for Novel Truncating Variants in the LMOD3 Gene as the Cause of Polyhydramnios in Two Successive Fetuses

“…To date, a total of 25 LMOD3 variants have been reported in the literature ( Supplementary Table S1 ). Of these, 4 missense variants, p.Arg83His, p.Glu142Asp, p.Lys282Glu, p.Pro552His, have been reported to cause Kleine-Levin syndrome (Al Shareef et al, 2019); a further two missense variants, p.Leu550Phe and p.Gln335Arg, have been associated with a mild form of congenital NM (Schatz et al, 2018) whereas a truncating variant, c.112delG (p.Glu38Lysfs*15), has been detected in a case without a definite clinical diagnosis (Theunissen et al, 2018). By contrast, the remaining 18 variants (i.e., variants highlighted in black in Figure 1B ) were reported to be causative for severe NM (Yuen et al, 2014; Abbott et al, 2017; Berkenstadt et al, 2018; Michael et al, 2019).…”

Nawracająca hipersomnia

“…Najwięcej białka zlokalizowano w móżdżku i jądrach podstawy, występuje ono też w korze mózgowej i hipokampie. Ponieważ białko leiomodina 3 należy do rodziny białek strukturalnych LMOD, regulowanych na etapie rozwoju zarodkowego, sugeruje się, że Nawracająca Hipersomnia może być neurorozwojową chorobą mózgu [9,10]. Dauvilliers i wsp.…”