Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM

Objective: The study aimed to show the clinical characteristics and prognosis of the L1 syndrome in patients with L1CAM mutations in the extracellular region.

Materials and Methods: Three affected boys and their siblings and parents from a large family were included in this study. Genetic etiology was investigated by whole-exome sequencing in the index patient. The pathogenic variant was detected by whole-exome sequencing and was validated by Sanger sequencing in 3 patients and other family members.

Results: We present 2 brothers and their cousin with prenatal onset hydrocephalus, severe developmental and speech delay, corpus callosum agenesis/hypogenesis, epilepsia, and adducted thumbs. A hemizygous missense mutation NM_024003 (c.A2351G:p.Y784C) on exon 18 of L1CAM gene was found in the 3 patients and their carrier mother. This missense mutation in the conserved region of the second fibronectin type III-like repeats located in the extracellular region of L1CAM resulted in the severe phenotype of X-linked inherited L1 syndrome in the patients.

Conclusion: L1 syndrome should be considered in the differential diagnosis of male children with intellectual disability, hydrocephalus, and adducted thumbs. While truncating mutations of L1CAM may cause a more severe phenotype, missense mutations cause milder forms. However, pathogenic missense mutations affecting key amino acid residues lead to severe phenotype likely

Cite this article as: Tüysüz B, Ercan-Şençiçek AG, Özer E, Goc N, Yalçınkaya C, Bilguvar K. Severe phenotype in patients with X-linked hydrocephalus caused by a missense mutation in L1CAM. Turk Arch Pediatr. 2022;57(5):521-525.