ClinGen Dosage Sensitivity Curation Page

L1CAM

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
19846429 Vos et al. (2010) reviewed the literature and described the L1CAM mutational spectrum. In this review, the authors document L1CAM variants identified in 143 different patients with L1 disease, including 36% missense mutations, 13% nonsense mutations, 24% deletions, 3% insertions, and 24% splice site changes. Genotype-phenotype correlations were proposed: variants leading to extracellular truncation of L1 protein are much more likely to produce a severe phenotype than missense mutations in the extracellular domains; mutations of the cytoplasmic domain tend to produce the mildest form of disease.
23820807 Adle-Biassette et al. (2013) described a large cohort of 138 cases with hydrocephalus and other neuropathological findings referred to their genetic testing laboratory for L1CAM sequencing. Fifty-seven cases had deleterious L1CAM variants. Among these fifty-seven cases, missense variants were detected in 16 patients (28.1 %), frameshift variants (small deletions, duplications, insertions) in 13 patients (22.8 %), splice variants in 14 patients (24.6 %), nonsense variants in 12 patients (21.0 %) and large rearrangements in 2 patients (3.5 %). Of note, case 14 includes triplication of whole L1CAM gene which is not clearly described.

Haploinsufficiency phenotype comments:

L1CAM encodes the L1 protein which is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules. Loss-of-function pathogenic variants in L1CAM have been associated with L1 syndrome. L1 syndrome includes X-linked hydrocephalus (OMIM 307000), MASA syndrome (OMIM 303350), X-linked complicated spastic paraplegia type 1 (OMIM 303350), and X-linked agenesis of the corpus callosum (OMIM 304100). L1 syndrome is an X linked intellectual disability syndrome and is characterized by hydrocephalus, agenesis or hypoplasia of corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. Loss-of-function of L1CAM is a well-known mechanism of L1 syndrome. Numerous pathogenic variants have been reported in the medical literature (PMIDs 29960101,11968085, etc.) and public/commercial variant databases. Genotype-phenotype correlation has been established based on literature review. Variants leading to extracellular truncation of L1 protein are much more likely to produce a severe phenotype than missense mutations in the extracellular domains; mutations of the cytoplasmic domain tend to produce the mildest form of disease.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
23820807 Adle-Biassette et al (2013) reported 1 single case (case 14) carrying a triplication of whole L1CAM gene among total 138 L1 sydrome patients cohort. However, no detail information about the breakpoints is included in this report.

Triplosensitivity phenotype comment:

There have not been any reports of focal duplications of the entire L1CAM gene that do not disrupt gene function. Larger duplications including L1CAM and other genes have been reported (PMID: 20860806, 18854860, 16080119).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.