L1CAM whole gene deletion in a child with L1 syndrome

Abstract

L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. 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.

Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation

“…This experimental design eliminates potentially confounding effects induced by genetic background changes or selection of cell clones. So far, hundreds of mutations in the L1CAM gene (which is X-chromosomal) were reported in patients with severe developmental malformations, neurological abnormalities, and intellectual disability ( Rosenthal et al, 1992 ; Stumpel and Vos, 1993 ; Jouet et al, 1994 , 1995 ; Fransen et al, 1997 ; Vos et al, 2010 ; Adle-Biassette et al, 2013 ; Chidsey et al, 2014 ). Most of the disease-causing L1CAM mutations likely represent loss-of-function mutations.…”

“…This spectrum includes the MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), hydrocephalus due to stenosis of the aqueduct of Sylvius, agenesis of the corpus callosum, and SPG1 (X-linked hereditary spastic paraplegia type 1), which are referred to collectively as CRASH syndrome ( Rosenthal et al, 1992 ; Stumpel and Vos, 1993 ; Jouet et al, 1994 , 1995 ; Fransen et al, 1997 ; Weller and Gärtner, 2001 ; Vos et al, 2010 ). Besides a reported whole gene deletion ( Chidsey et al, 2014 ), these mutations include frameshift, nonsense, and missense mutations, resulting in the production of truncated proteins or proteins with mutations in structurally defined key residues ( Stumpel and Vos, 1993 ). Missense mutations most likely lead to alterations of intracellular trafficking and impaired function and mobility caused by additional cysteines on the surface of the molecule or aberrant ligand binding ( De Angelis et al, 1999 , 2002 ; Kenwrick et al, 2000 ; Schäfer et al, 2010 ).…”

MASA syndrome in twin brothers: case report of sixteen-year clinical follow up

“…This would result in the L1 failing to remain associated with the cell surface due to the loss of its transmembrane domain. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed (7). The intronic mutation IVS27-12G→A detected in our patients was diagnosed by Brunner-Krainz et al (8) 9).…”

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

“…It is a recessive X-linked disorder that is exclusively affects men with incidence of 1/30.000 male births (5), and it is caused by mutations in the L1CAM gene (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) located near the telomere of the long arm of X chromosome in Xq28 in humans (20)(21)(22). Over 200 mutations in L1CAM gene have been reported (3,17), this gene encodes for the L1 Cell Adhesion Molecule protein, which is a member of the immunoglobulin superfamily. As the name implies; the protein enables the adhesion of neural cells to one another and it is a key regulator of synapse formation, synaptic plasticity and axons and dendrites growth and formation (23)(24)(25)(26).…”