title: A De Novo Mutation in TEAD1 Causes Non-X-Linked Aicardi Syndrome.
abstract: OBJECTIVE
  Aicardi syndrome (AIC) is a congenital neurodevelopmental disorder characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. Variation in phenotype and disease severity is well documented, but chorioretinal lacunae represent the most constant pathological feature. Aicardi syndrome is believed to be an X-linked-dominant disorder occurring almost exclusively in females, although 46, XY males with AIC have been described. The purpose of this study is to identify genetic factors and pathways involved in AIC.
  
  
  METHODS
  We performed exome/genome sequencing of 10 children diagnosed with AIC and their parents and performed RNA sequencing on blood samples from nine cases, their parents, and unrelated controls.
  
  
  RESULTS
  We identified a de novo mutation in autosomal gene TEAD1, expressed in the retina and brain, in a patient with AIC. Mutations in TEAD1 have previously been associated with Sveinsson's chorioretinal atrophy, characterized by chorioretinal degeneration. This demonstrates that TEAD1 mutations can lead to different chorioretinal complications. In addition, we found that altered expression of genes associated with synaptic plasticity, neuronal development, retinal development, and cell cycle control/apoptosis is an important underlying potential pathogenic mechanism shared among cases. Last, we found a case with skewed X inactivation, supporting the idea that nonrandom X inactivation might be important in AIC.
  
  
  CONCLUSIONS
  We expand the phenotype of TEAD1 mutations, demonstrate its importance in chorioretinal complications, and propose the first putative pathogenic mechanisms underlying AIC. Our data suggest that AIC is a genetically heterogeneous disease and is not restricted to the X chromosome, and that TEAD1 mutations may be present in male patients.
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States 3Department of Medical Genetics, U.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Siniard
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kurdoglu
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Richholt
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: De Both
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Malenica
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Sampathkumar
authors.initials: S
authors.lastname: Rangasamy
authors.affiliation: Phoenix Children's Hospital, Phoenix, Arizona, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Kulkarni
authors.affiliation: Phoenix Children's Hospital, Phoenix, Arizona, United States.
authors.forename: Saunder
authors.initials: S
authors.lastname: Bernes
authors.affiliation: Alberta Children's Hospital, University of Calgary, Alberta, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Buchhalter
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Keri
authors.initials: K
authors.lastname: Ramsey
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Narayanan
authors.affiliation: Dorrance Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, Arizona, United States 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
mesh_terms: D000328:Adult; D058540:Aicardi Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors