title: Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.
abstract: Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited genetic multisystem developmental condition with considerable phenotypic and allelic heterogeneity. Missense and in-frame deletions within the SMC1A gene can be associated with epilepsy and milder craniofacial features. We report two females who presented with developmental delay and developed isolated medically refractory seizures with unrevealing initial laboratory, imaging and genetic evaluations. Whole exome sequencing (WES) analyses were performed and were instrumental in uncovering the genetic etiology for their conditions. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. We also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. We review previous reports of SMC1A mutations with epilepsy. SMC1A should be included in clinical gene panels for early infantile and early childhood epileptic encephalopathy.
authors.affiliation: Pediatric Neurology, Department of Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jessica H R
authors.initials: JH
authors.lastname: Goldstein
authors.affiliation: Center for Human Genetics, Departments of Genetics and Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Thipwimol
authors.initials: T
authors.lastname: Tim-Aroon
authors.affiliation: Institute of Human Genetics and Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shieh
authors.affiliation: Center for Human Genetics, Departments of Genetics and Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Merrill
authors.affiliation: Center for Human Genetics Laboratory, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Deeb
authors.affiliation: Center for Human Genetics Laboratory, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pediatric Neurology, Department of Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Bass
authors.affiliation: Center for Human Genetics, Departments of Genetics and Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA. Electronic address: jirair.bedoyan@uhhospitals.org.
authors.forename: Jirair K
authors.initials: JK
authors.lastname: Bedoyan
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003635:De Lange Syndrome / Q000175:diagnosis / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008969:Molecular Sequence Data; D013577:Syndrome; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000098550:Structural Maintenance of Chromosome Protein 1
keywords: Cornelia de Lange syndrome; SMC1A; Status epilepticus; Whole exome sequencing