title: Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies.
abstract: OBJECTIVE
  To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations.
  
  
  METHODS
  Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio.
  
  
  RESULTS
  We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R).
  
  
  CONCLUSIONS
  This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders.
authors.affiliation: David Geffen School of Medicine at UCLA (C.S.), Los Angeles, CA; and Division of Clinical Neuroradiology and Interventional Neuroradiology (F.M.), Division of Clinical Genetics and Dysmorphology (J.M.G.), Department of Pediatrics (J.M.G., V.W.), Department of Pediatrics and Neurology (T.M.P.), and Board of Governors Regenerative Medicine Institute (T.M.P.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Christine
authors.initials: C
authors.lastname: Shieh
authors.affiliation: David Geffen School of Medicine at UCLA (C.S.), Los Angeles, CA; and Division of Clinical Neuroradiology and Interventional Neuroradiology (F.M.), Division of Clinical Genetics and Dysmorphology (J.M.G.), Department of Pediatrics (J.M.G., V.W.), Department of Pediatrics and Neurology (T.M.P.), and Board of Governors Regenerative Medicine Institute (T.M.P.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Franklin
authors.initials: F
authors.lastname: Moser
authors.affiliation: David Geffen School of Medicine at UCLA (C.S.), Los Angeles, CA; and Division of Clinical Neuroradiology and Interventional Neuroradiology (F.M.), Division of Clinical Genetics and Dysmorphology (J.M.G.), Department of Pediatrics (J.M.G., V.W.), Department of Pediatrics and Neurology (T.M.P.), and Board of Governors Regenerative Medicine Institute (T.M.P.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.affiliation: David Geffen School of Medicine at UCLA (C.S.), Los Angeles, CA; and Division of Clinical Neuroradiology and Interventional Neuroradiology (F.M.), Division of Clinical Genetics and Dysmorphology (J.M.G.), Department of Pediatrics (J.M.G., V.W.), Department of Pediatrics and Neurology (T.M.P.), and Board of Governors Regenerative Medicine Institute (T.M.P.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Watiker
authors.affiliation: David Geffen School of Medicine at UCLA (C.S.), Los Angeles, CA; and Division of Clinical Neuroradiology and Interventional Neuroradiology (F.M.), Division of Clinical Genetics and Dysmorphology (J.M.G.), Department of Pediatrics (J.M.G., V.W.), Department of Pediatrics and Neurology (T.M.P.), and Board of Governors Regenerative Medicine Institute (T.M.P.), Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Tyler Mark
authors.initials: TM
authors.lastname: Pierson