Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis

Abstract

Objective To identify genes underlying childhood onset psychosis. Methods Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors. Results We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder. Conclusions This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

“…Some of these disease-causing mutations were found in the vicinity of sequences that are mutated in the L1/858-863 mice. A patient with p.Arg846His mutation of L1, which is close to the position mutated in the L1/858-863 mice, displayed childhood onset hyperactivity, psychosis and autism spectrum disorder with symptoms overlapping with those seen in obsessive-compulsive disorders [74]. Interestingly, in mice treated with lipopolysaccharide, social withdrawal and increased stereotype activity in males was linked to a reduced number and volume of Reelin expressing cells, to a reduced expression of trans-synaptic cell-adhesion molecules and to alterations in spine density [76].…”

“…Our results are in agreement with the findings that the multiple mutations in L1 lead to different disease outcomes with different severity in humans [69][70][71] (see also http: //www.l1cammutationdatabase.info/; access date 10 January 2023). Several mutations in the FNIII-like domains are disease-causing in humans (see for instance: [71][72][73][74][75]). Some of these disease-causing mutations were found in the vicinity of sequences that are mutated in the L1/858-863 mice.…”

Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities

“…Since obsessive-compulsive behavior and altered reaction to novelty are common in patients with autism spectrum disorders, and since L1 syndrome can also be associated with autistic-like behavior in humans and mice [33,51,[72][73][74][75][76], we examined L1/687 mice in the marble burying test to evaluate digging activity, to observe repetitive and compulsive-like behaviors or changes in anxiety, activity and novel object recognition. Mice were placed in a cage containing high bedding with 20 black marbles on top.…”