Two novel pathogenic variants of L1CAM gene in two fetuses with isolated X‑linked hydrocephaly: A case report

Abstract

Hydrocephalus due to aqueductal stenosis (HSAS; Online Mendelian Inheritance in Man #307000) is a rare X-linked, recessively-inherited disease characterized by severe hydrocephaly and occasionally adducted thumbs, in addition to intellectual disability and spasticity in surviving individuals. The present study described two fetuses with severely enlarged ventricles of the brain. The clinical diagnosis of HSAS was made on the basis of family history and sonographic findings. Molecular testing of the L1 cell adhesion molecule (L1CAM) gene revealed two novel hemizygous L1CAM variants, c.998C>T(p.Pro333Leu) and c.2362G>T(p.Val788Phe). The variants affect the highly conserved amino acids which are located in the key domains of the protein (the fourth Ig domain and second FnIII domain, respectively). The two variants were predicted to be 'disease causing' by a number of prediction tools, and have been classified as likely pathogenic following the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. The present study highlights the importance of combining family history, prenatal ultrasonography and molecular testing in the diagnosis of HSAS. The novel variants expand the mutational spectrum of L1CAM gene in the Chinese population, and could be used in genetic counseling, carrier testing of female relatives, and prenatal, as well as preimplantation genetic diagnosis.

Exome Sequencing as a Potential Diagnostic Adjunct in Sporadic Congenital Hydrocephalus

“…Novel L1CAM mutations included the p.Trp460Cys and p.Trp635Arg deleterious missense mutations, mapping to the fifth (of 6) immunoglobulin-like domain and the first (of 5) extracellular fibronectin domain, respectively; 2 splice site mutations, c.1828 + 1G>A (localizing to intron 15) and c.1546 + 1G>T (located in intron 13) were associated with loss-of-function translation frameshifts; and the stop-gain mutation p.Glu304X. The previously reported deleterious missense mutation p.Val788Phe (localizing to the second fibronectin domain), and the known splice site mutation c.806 + 1G>C (positioned in intron 8), were also identified (Figure). All 6 patients for whom clinical information was available had neurodevelopmental delays.…”

Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review

“…Of particular interest, our literature review indicated that among the known genes for AR-HSPs, the most reported CNVs in SPG11 and SPG7 have been mainly linked to the HSP phenotype. Also, CNVs in PLP1 are not an important cause of X-linked SPG2, but CNVs in L1CAM play a crucial role in the development of SPG1 [Kutsche et al, 2002;Xie et al, 2018]. Despite all these informative findings, the exact proportion of HSP cases caused by CNVs and the extent to which these CNVs implicate HSP pathophysiology are yet to be determined.…”

“…Table S1). SPG1/L1CAM (OMIM # 303350) In SPG1 patients, the two most prevalent types of reported L1CAM variants have been missense and rearrangements [Kutsche et al, 2002;Xie et al, 2018]. The compact gene structure and the low density of repeats in the genomic L1CAM DNA sequence predispose this gene to illegitimate recombination and consequent rearrangements including loss of the complete gene [Kutsche et al, 2002].…”

X‐ray structure and function of fibronectin domains two and three of the neural cell adhesion molecule L1

“…[18][19][20] Mutations located in the L1 extracellular regions generally correlate with a more severe phenotype than mutations in the cytoplasmic tail (http://www.l1cam mutat ionda tabase.info/). [21][22][23][24][25] So far, high resolution structural information on fulllength L1 or fragments containing two or more domains of L1's extracellular part has not been obtained. Structural information has mainly been inferred by comparison with other, homologous proteins and from studies mapping functional domains or binding sites within L1 or related proteins.…”

“…Mutations located in the L1 extracellular regions generally correlate with a more severe phenotype than mutations in the cytoplasmic tail (http://www.l1cammutationdatabase.info/). 21–25 …”