Pathogenic variants in
L1CAM, the gene encoding the
L1 cell adhesion molecule, are responsible for a wide clinical spectrum including X-linked hydrocephalus with
stenosis of the Sylvius aqueduct,
MASA syndrome (
mental retardation,
aphasia,
shuffling gait, adducted thumbs), and a form of
spastic paraplegia (
SPG1). A moderate phenotype with mild
intellectual disability (ID) and X-linked partial
corpus callosum agenesis (CCA) has only been related to
L1CAM in one family. We report here a second family, including 5 patients with mild to moderate ID and partial CCA without signs usually associated with
L1CAM pathogenic variations (such as
hydrocephalus, pyramidal syndrome, thumb adductus,
aphasia). We identified a previously unreported c.3226A > C transversion leading to a p.Thr1076Pro amino acid substitution in the fifth fibronectin type III domain (FnIII) of the
protein which co-segregates with the phenotype within the family. We performed in vitro assays to assess the pathogenic status of this variation. First, the expression of the novel p.Thr1076Pro mutant in COS7 cells resulted in endoplasmic reticulum (ER) retention and reduced
L1CAM cell surface expression, which is expected to affect both L1CAM-mediated cell-cell adhesion and neurite growth. Second, immunoblotting techniques showed that the immature form of the
L1CAM protein was increased, indicating that this variation led to a lack of maturation of the
protein. ID associated with CCA is not a common clinical presentation of
L1CAM pathogenic variants. Genome-wide analyses will identify such variations and it is important to acknowledge this atypical phenotype.