Variants in L1CAM have been observed in individuals with L1 syndrome (includes brain abnormalities, intellectual disability, and movement problems), hydrocephalus, and Hirschsprung disease. These phenotypic features are only present in males. L1CAM was first reported in relation to the constellation of phenotypic features related to X-linked recessive L1 syndrome in 1992 (Rosenthal et al., 1303258). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.The mechanism for disease is hemizygous loss of function.There have been over 200 L1CAM mutations reported, including nonsense, frameshift, splicing, and missense variants, as well as large duplications and deletions (19846429, 9268105, 12725590, 10797421). Variants in this gene segregated with disease in at least 40 additional family members. This gene-disease association is supported by animal models (19565280). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. In summary, L1CAM is definitively associated with X-linked recessive L1 syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 10/2/2019 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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