L1 Syndrome Prenatal Diagnosis Supplemented by Functional Analysis of One L1CAM Gene Missense Variant

L1 syndrome, a complex X-linked neurological disorder, is caused by mutations in the L1 cell adhesion molecule (L1CAM) gene. L1CAM molecule is a member of immunoglobulin (Ig) superfamily of neural cell adhesion molecules (CAMs), which plays a pivotal role in the developing nervous system. In this study, a L1CAM gene exonic missense variant (c.1108G > A, p.G370R) was identified in two induced fetuses (abnormal fetuses), who presented corpus callosum agenesis accompanied with hydrocephalus. Clinical data, published literature, online database, and bioinformatic analysis suggest that the single-nucleotide variant of L1CAM gene is a likely pathogenic mutation. In vitro assays were performed to evaluate the effects of this variant. Based on NSC-34/COS-7 cells transfected with wild-type (L1-WT) and mutated (L1-G370R) plasmids, the L1CAM gene exonic missense variant (c.1108G > A, p.G370R) reduced cell surface expression, induced partial endoplasmic reticulum retention, affected posttranslational modification, and reduced protein’s homophilic adhesive ability, but did not induce endoplasmic reticulum stress, which might probably associate with L1 syndrome. Finally, 35 isolated fetuses were screened for L1CAM gene variants by Sanger sequencing. These cases all prenatally suspected of corpus callosum agenesis accompanied with hydrocephalus, which may relate to L1 syndrome. Consequently, one L1CAM gene single missense variant (c.550C > T, p.R184W) was detected in one fetus. Our results provided evidence that the L1CAM gene missense variant (c.1108G > A, p.G370R) may relate to L1 syndrome. The findings of this study suggest a potential possibility of L1CAM gene screening for prenatal diagnoses for fetuses presented corpus callosum agenesis accompanied with hydrocephalus.

Neurodevelopmental Outcomes following Prenatal Diagnosis of Isolated Corpus Callosum Agenesis: A Systematic Review

Abnormalities of corpus callosum are one of the most common brain anomalies. Fetuses with isolated corpus callosum agenesis (CCA) have a better prognosis than those with additional anomalies. However, unpredictable neurodevelopmental outcomes of truly isolated CCA make prenatal counseling a challenge. The aim of this review is to evaluate neurodevelopmental outcomes in children with prenatal diagnosis of isolated CCA. Controlled clinical trials published between May 23, 2009, and May 23, 2019, using the MeSH term “agenesis of corpus callosum” were reviewed. A total of 942 articles were identified, and 8 studies were included in the systematic review depending on the inclusion criteria. These studies included 217 fetuses with isolated CCA and no other anomalies at prenatal assessment. Neurodevelopmental outcome was reported to be normal in 83 children with a prenatal diagnosis of isolated CCA confirmed at birth within 128 completed assessments. About 45 children presented borderline, moderate, or severe neurodevelopmental outcome. In this review, neurodevelopment was favorable in two-thirds of the cases, but mild disabilities emerged in older children. Despite this, disabilities can occur later beyond school age and a low risk of severe cognitive impairment exists. Our study highlights the essential early diagnosis and proper supportive therapy.