L1 Syndrome-Associated Phenotypes and a Novel L1CAM Variant: A Clinical Report

Abstract

L1 syndrome is a group of X-linked diseases caused by pathogenic variants in the human L1 cell adhesion molecule gene (L1CAM; OMIM 308840). The L1CAM gene is expressed primarily in the nervous system, where it plays important roles in neuronal development, including the guidance of neurite outgrowth, neuronal cell migration, axon bundling, synaptogenesis, myelination, neuronal cell survival, and long-term potentiation. L1 syndrome comprises a group of overlapping phenotypes including partial agenesis of corpus callosum, congenital X-linked hydrocephalus, and mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome. Molecular analysis was performed in four patients with congenital hydrocephalus (CH) and adducted thumbs. Three pathogenic variants were identified in the L1CAM gene, novel c.539dupA (p.Gln181Alafs*46) common to the two siblings, c.791G > A (p.Cys264Tyr) and c.1453C > T (p.Arg485*) variants. A correlation between genotype and phenotype has been reported in L1-related disorders. Two families with intrafamilial variability are presented and a novel pathogenic variant in the L1CAM gene has been reported. L1 syndrome should be considered primarily in patients with CH and adducted thumbs.

Keywords

L1 syndrome - L1CAM gene - congenital hydrocephalus - adducted thumbs

• References

• 1 Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nat Genet 1992; 2 (02) 107-112
• 2 Chidsey BA, Baldwin EE, Toydemir R, Ahles L, Hanson H, Stevenson DA. L1CAM whole gene deletion in a child with L1 syndrome. Am J Med Genet A 2014; 164A [phone]
• 3 Marín R, Ley-Martos M, Gutiérrez G, Rodríguez-Sánchez F, Arroyo D, Mora-López F. Three cases with L1 syndrome and two novel mutations in the L1CAM gene. Eur J Pediatr 2015; 174 (11) 1541-1544
• 4 Vos YJ, de Walle HEK, Bos KK. et al. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. J Med Genet 2010; 47 (03) 169-175
• 5 Bousquet I, Bozon M, Castellani V. et al. X-linked partial corpus callosum agenesis with mild intellectual disability: identification of a novel L1CAM pathogenic variant. Neurogenetics 2021; 22 (01) 43-51
• 6 Fransen E, van Camp G, Vits L, Willems PJ, van Camp Vits PJ, Willems GL, Willems P. Genotype-Phenotype Correlation in Li Associated Diseases. Vol 35.; 1998 Accessed March 31, 2024 at: http://dnalab-www.uia.ac.be/dnalab/ll/
• 7 Ochando I, Vidal V, Gascón J, Acién M, Urbano A, Rueda J. Prenatal diagnosis of X-linked hydrocephalus in a family with a novel mutation in L1CAM gene. J Obstet Gynaecol 2016; 36 (03) 403-405
• 8 Jouet M, Rosenthal A, MacFarlane J, Kenwrick S, Donnai D. A missense mutation confirms the L1 defect in X-linked hydrocephalus (HSAS). Nat Genet 1993; 4 (04) 331
• 9 Weller S, Gärtner J. Genetic and Clinical Aspects of X–Linked Hydrocephalus (L1 Disease): Mutations in the L1CAM Gene. Vol 18.; 2001 Accessed March 31, 2024 at: http://dnalab-www.uia.ac.be/dnalab/l1/
• 10 Jouet M, Rosenthal A, Armstrong G. et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994; 7 (03) 402-407
• 11 Rünker AE, Bartsch U, Nave KA, Schachner M. The C264Y Missense Mutation in the Extracellular Domain of L1 Impairs Protein Trafficking In Vitro and In Vivo.; 2002. Accessed March 31, 2024 at: http://dnalab-www.uia.ac.be/dnalab/l1/
• 12 Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10 (06) 845-858
• 13 Adle-Biassette H, Saugier-Veber P, Fallet-Bianco C. et al. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. Acta Neuropathol 2013; 126 (03) 427-442