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.

A truncation mutation in the L1CAM gene in a child with hydrocephalus

<abstract> <p>Hydrocephalus is a neurodevelopmental, X-linked recessive disorder caused by mutations in the <italic>L1CAM</italic> gene. The <italic>L1CAM</italic> gene encodes for L1CAM protein which is essential for the nervous system development including adhesion between neurons, Myelination, Synaptogenesis etc. Herein, the present study has reported mutations in L1 syndrome patient with Hydrocephalus and Adducted thumb. Genomic DNA was extracted from patients whole blood (n = 18). The 11 exons of the <italic>L1CAM</italic> gene were amplified using specific PCR primers. The sequenced data was analysed and the pathogenicity of the mutation was predicted using the various bioinformatics programs: PROVEAN, PolyPhen2, and MUpro. The results revealed that the proband described here had nonsense mutation G1120→T at position 1120 in exon 9 which is in extracellular immunoglobulin domain (Ig4) of the <italic>L1CAM</italic> gene. This nonsense mutation is found to be truncated with a deleterious effect on developing brain of the child, and this is the first report of this novel mutation in patient with X-linked Hydrocephalus in India.</p> </abstract>

Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis

Context Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. Objective We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. Patients The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. Results Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. Conclusion We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.

Comprehensive bioinformatics analysis ofL1CAMgene revealed Novel Pathological mutations associated with L1 syndrome

BackgroundMutations in the human L1CAM gene cause a group of neurodevelopmental disorders known as L1 syndrome (CRASH syndrome). The L1CAM gene provides instructions for producing the L1 protein, which is found all over the nervous system on the surface of neurons. L1 syndrome involves a variety of characteristics but the most common characteristic is muscle stiffness. Patients with L1 syndrome can also suffer from difficulty speaking, seizures, and underdeveloped or absent tissue connecting the left and right halves of the brain.MethodThe human L1CAM gene was studied from dbSNP/NCBI, 1499 SNPs were Homo sapiens; of which 450 were missense mutations. This selected for Comprehensive bioinformatics analysis by several in silico tools to investigate the effect of SNPs on L1CAM protein’s structure and function.Results34 missense mutations (26 novel mutations) out of 450 nsSNPs that are found to be the most deleterious that effect on the L1CAM structural and functional level.ConclusionBetter understanding of L1 syndrome caused by mutations in L1CAM gene was achieved using Comprehensive bioinformatics analysis. These findings describe 35 novel L1 mutations which improve our understanding on genotype-phenotype correlation. And can be used as diagnostic markers for L1 syndrome and besides in cancer diagnosis specifically in breast cancer.