title: Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia.
abstract: We report a case of an infant with unique and unreported combinations of brain anomalies. The patient showed distinctive facial findings, severe delay in psychomotor development, cranial nerve palsy and seizures. Brain magnetic resonance imaging performed at 5 days of age revealed complex brain malformations, including heterotopia around the mesial wall of lateral ventricles, dysmorphic cingulate gyrus, and enlarged midbrain tectum. The patient unexpectedly died at 13 months of age. Postmortem pathological findings included a polymicrogyric cingulate cortex, periventricular nodular heterotopia, basal ganglia and thalamic anomalies, and dysmorphic midbrain tectum. Potential candidate genes showed no abnormalities by traditional PCR-based sequencing. Whole-exome sequencing confirmed the presence of novel gene variants for filamin B (FLNB), guanylate binding protein family member 6, and chromosome X open reading frame 59, which adapt to the autosomal recessive mode or X-linked recessive mode. Although immunohistochemical analysis confirmed the expression of FLNB protein in the vessel walls and white matter in autopsied specimens, there may be functional relevance of the compound heterozygous FLNB variants during brain development.
authors.affiliation: Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Okumura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimojima
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ikeno
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Takanashi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Hisata
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Shoji
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.forename: Toru
authors.initials: T
authors.lastname: Furukawa
authors.forename: Tetsuko
authors.initials: T
authors.lastname: Kishida
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D059472:Exome; D064448:Filamins / Q000235:genetics*; D006179:Gyrus Cinguli / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000175:diagnosis* / Q000235:genetics; D054091:Periventricular Nodular Heterotopia / Q000175:diagnosis* / Q000235:genetics; D003336:Tectum Mesencephali / Q000473:pathology*
chemical_list: D064448:Filamins