Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.
Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC).
We combined clinical data, in silico effect predictions and functional analysis of four L1CAM variants, p.I37N, p.T38M, p.M172I and p.D202Y, located to the two N-terminal Ig-like domains present in five families with symptoms of L1 syndrome.
The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus.
MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs.
The poly-ubiquitination of L1-W635C and its association with the ER chaperone calnexin provide further insights into the molecular mechanisms underlying defective cell surface trafficking of L1CAM in L1 syndrome.
L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.
Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome).
However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1.
Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild-moderate intellectual disability without obvious L1 syndrome features.
Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1.
Mutations in the gene encoding the neuronal cell adhesion molecule L1 are responsible for several syndromes with clinical overlap, including X-linked hydrocephalus (XLH, HSAS), MASA (mental retardation, aphasias, shuffling gait, adducted thumbs) syndrome, complicated X-linked spastic paraplegia (SP 1), X-linked mental retardation-clasped thumb (MR-CT) syndrome, and some forms of X-linked agenesis of the corpus callosum (ACC).
X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders.
This was confirmed by identification of mutations in patients with X linked hydrocephalus and MASA syndrome within the gene for neural cell adhesion molecule L1.