L1 Syndrome via the L1CAM Gene

L1 syndrome is a neurological spectrum disorder that frequently presents as congenital hydrocephalus and adducted thumbs in males. However, this disorder spans a broad continuum of clinical severity, ranging from prenatal death to very mildly affected, and may or may not include these two classic features. Due to the high clinical variability, this spectrum disorder is divided into four clinical sub-types. At the most severe end of the L1 spectrum is X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius, sometimes called HSAS syndrome [for Hydrocephalus, Stenosis, Adducted thumbs, and Spasticity]. This form of the disorder may be detected prenatally, and can result in prenatal death. Alternatively, some individuals with HSAS may be born with or develop varying degrees of hydrocephalus and moderate to profound intellectual disability. Adducted thumbs are a key feature pointing to the L1CAM gene as the cause, but this feature is only observed in ~50% of cases. This can range to a milder form of L1 syndrome, sometimes called MASA syndrome [standing for Mental retardation, Aphasia, Spastic paraplegia, and Adducted thumbs]. Clinical features of this disorder are similar to HSAS, but often become apparent later in development and are less severe.

Two other documented forms of L1 syndrome are spastic paraplegia type one, which includes spasticity and intellectual disability, but no obvious brain abnormalities; and X-linked corpus callosum dysgenesis, in which corpus callosum abnormalities (but not hydrocephalus) accompany spasticity and intellectual disability (Jouet et al. 1994. PubMed ID: 7920659; Fransen et al. 1997. PubMed ID: 9300653). The acronym CRASH [Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spasticity, and Hydrocephalus] is an outdated term initially intended to encompass the full clinical spectrum of L1 Syndrome (Stumpel and Vos. 2015. PubMed ID: 20301657). Additional phenotypes that can accompany these five classic primary features of L1 syndrome include seizures, Hirschprung disease, talipes equinovarus, pes planus, shuffling gait, early hypotonia, kyphosis, lordosis, and macro or micro-cephaly. Importantly, the features of this disease are variable even among family members who carry the same pathogenic variant (Fransen et al. 1995. PubMed ID: 8556302; Finckh et al. 2000. PubMed ID: 10797421).

While males are disproportionately affected, ~5% of female carriers have clinical features. In the small number of females documented as affected, adducted thumbs and mild intellectual disability are the most commonly reported features; however, brain defects including severe hydrocephalus resulting in prenatal death have been reported. X-inactivation skewing is predicted to play a role in the severity of female phenotypes (Kaepernick et al. 1994. PubMed ID: 8062435; Stumpel and Vos. 2015. PubMed ID: 20301657). In males, L1 syndrome, accounts for 5-10% of nonsyndromic congenital hydrocephalus, and has an estimated prevalence of 1 in 30,000 (Stumpel and Vos. 2015. PubMed ID: 20301657). HSAS is the most commonly reported form in males.

Currently, there are no treatments for L1 syndrome, yet advantages of testing may include: 1) prognostic information, such as reported genotype-phenotype correlations to predict the expected severity of the disorder for a given patient, 2) early identification and treatment of symptoms such as hydrocephalus and seizures, 3) prenatal testing or pre-implantation genetic diagnosis for future pregnancies in families with inherited causative variants, or 4) knowledge of a de novo variant decreasing anxiety for future reproductive planning due to reduced recurrence risk.

L1 syndrome is an X-linked recessive disorder caused by pathogenic variants in the L1CAM gene. Pathogenic missense, nonsense, frameshift and splicing variants, as well as CNV events have been reported in L1CAM, and all variant types are spread widely across the gene (Jouet et al. 1994. PubMed ID: 7920659; Vos and Hofstra. 2010. PubMed ID: 19953645). Indeed, the L1CAM gene as a whole is intolerant to both loss of function and missense variation in the heterozygous state (https://gnomad.broadinstitute.org/gene/ENSG00000198910). De novo variants are detected in ~7% of cases, and maternal germline mosaicism has also been reported (Vos et al. 2010. PubMed ID: 19846429). Genotype-Phenotype correlations observed include earlier death among patients with loss of function (early protein termination) variants, compared to missense variants, and further indicate that variants in the large extracellular domain of the protein tend to cause a more severe phenotype than variants located in the cytoplasmic domain (Vos et al. 2010. PubMed ID: 19846429; Weller and Gärtner. 2001. PubMed ID: 11438988). A large majority of pathogenic variants in L1CAM are private (non-recurrent variants detected in single families; http://www.l1cammutationdatabase.info/), and the most commonly reported pathogenic variants are still frequently absent from the gnomAD database or detected at a very low rate (0.001% variant allele frequency)(Human Gene Mutation Database, HGMD; gnomAD database, gnomAD.broadinstitute.org). While variable expressivity, including intrafamilial variability, is well documented for L1 Syndrome, disease penetrance is thought to be complete for males (Stumpel and Vos. 2015. PubMed ID: 20301657).

L1CAM encodes the neuronal cell adhesion molecule L1. L1 is an axonal glycoprotein that consists of a large extracellular part possessing six immunoglobulin-like and five fibronectin-repeat domains, which is linked via a single transmembrane sequence to a short cytoplasmic region. L1 plays an important role in nervous system development and function, acting in neuronal migration and differentiation, axon growth and synapse formation, cell adhesion, and cell-cell communication (Schmid and Maness. 2008. PubMed ID: 18760361; Samatov et al. 2016. PubMed ID: 27267927). Numerous cell culture and animal models have been developed for the L1CAM gene, and have been helpful for studying the molecular etiology of L1 syndrome (Patzke et al. 2016. PubMed ID: 27001749).

The clinical sensitivity of this test depends on the relevant clinical characteristics and family history of each patient. Four classic features - hydrocephalus, adducted thumbs, aqueductal stenosis, and dysgenesis of the corpus callosum, are important for determining the clinical sensitivity of L1CAM testing. If three or more of these characteristics are observed, and if the patient has two or more affected family members, clinical sensitivity is predicted to be over 85%. However, if less than three of these characteristics are present, and there is no family history of L1 syndrome, clinical sensitivity is expected to be around 10% (Vos et al. 2010. PubMed ID: 19846429). Analytical sensitivity of this test is predicted to be very high (>99%). A large majority of reported pathogenic variants in this gene are single nucleotide variants or small deletions/duplications, which this test is expected to detect all. Several gross deletion and duplication copy number variants (CNV events) have also been reported, and this test is predicted to detect a great majority of this type of variant as well.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the L1CAM gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.