Novel L1CAM splice site mutation in a young male with L1 syndrome

The L1 cell adhesion molecule gene (L1CAM) is located in band Xq28 and consists of 28 exons [NC_000023. 10, isoform 1, NCBI], which code for a transmembrane glycoprotein belonging to the immunoglobulin superfamily [Moos et al., 1988; Djabali et al., 1990]. The L1CAM protein is predominantly expressed in the nervous system [Kenwrick et al., 2000] and has been implicated in several central nervous system development processes including neuronal migration [Lindner et al., 1983], neurite outgrowth [Lagenaur and Lemmon, 1987] and fasciculation [Stallcup and Beasley, 1985], myelination [Wood et al., 1990], synaptogenesis, and growth cone morphology [Burden-Gulley et al., 1995]. Mutations in L1CAM cause an X-linked recessive disorder called L1 syndrome. Major features include congenital hydrocephalus, adducted thumbs, spastic paraplegia, agenesis of the corpus callosum, and cognitive impairment [Finckh et al., 2000]. L1CAM mutations are also known to cause milder phenotypes including hydrocephalus, MASA syndrome, spastic paraplegia type 1, and agenesis of the corpus callosum. These disorders have been consolidated and are now considered to be manifestations of L1 syndrome [Kanemura et al., 2006]. Here, we report the identification of a novel splice site mutation in L1CAM involving the cytoplasmic domain of themature protein in a boy with L1 syndrome. The patient was born in 1986 as the second child of healthy nonconsanguineous Swedish parents.Hydrocephaluswas first detected by fetal ultrasound at 36 weeks gestation. The boy was delivered at 38 weeks gestation by Caesarean. Hydrocephalus, mild global hypotonia, and bilateral adducted thumbs were noted soon after birth. He had a ventriculo-peritoneal shunt placed at 2 days of age. Chromosome analysis of lymphocytes showed a normal 46,XY karyotype. Cognitive impairment was detected during his early childhood. The family history showed two deceased maternal uncles with hydrocephalus, cognitive impairment, spastic paraplegia, and adducted thumbs (Fig. 1). The patient’s mother was concerned about an inherited disease and asked for genetic assessmentwhen the patientwas 20 years old andhis older sisterwas 23 years old. Upon evaluation, L1 syndrome was suspected and sequencing of L1CAM was performed [Methods are described in the supporting information in the online issue, which is available at wileyonlinelibrary.com]. Blood samples were obtained from the patient, his mother, maternal grandmother, and sister forDNAextraction and sequencing of the L1CAM gene. Dideoxynucleotide sequencing showed a hemizygous c.3458-1G>C variant in the patient. The patient’s mother, grandmother, and sister were all heterozygous for the same mutation (Fig. 1). The results were verified by sequencing of the complete L1CAM gene performed by the external laboratory Centogene (Rostock, Germany). This mutation has not been reported previously. It predicts a deletion of exon 26 in the RNA splicing process, which, in turn, should cause a frameshift in exons 27 and 28. The mutation can be inferred to cause a loss of function of most of the cytoplasmic domain of the protein. Alternatively, the variant may cause nonsense-mediated mRNA decay. The cytoplasmic domain of L1CAM ismultifunctional [Fransen et al., 1998]. It provides an anchor to the cytoskeleton via ankyrin [Hortsch, 1996] and this interaction has been reported to be required for the initial protrusion of axons from the neuronal soma [Nishimura et al., 2003]. Disturbance of these functions of the L1CAM cytoplasmic domain is a likely cause of the symptoms related to axon growth that occur in L1 syndrome. The cytoplasmic domain contains serine phosphorylation sites [Hortsch, 1996]. Phosphorylation may be a way for modulation of L1CAM signal transducing activity [Schuch et al., 1989; Kunz et al., 1996; Wong et al., 1996a,b] and for the initiation of intracellular second messenger cascades [Schuch et al., 1989; Williams et al.,