title: Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability.
abstract: BACKGROUND
  De novo mutations are emerging as an important cause of neurocognitive impairment, and whole exome sequencing of case-parent trios is a powerful way of detecting them. Here, we report the findings in four such trios.
  
  
  METHODS
  The Deciphering Developmental Disorders study is using whole exome sequencing in family trios to investigate children with severe, sporadic, undiagnosed developmental delay. Three of our patients were ascertained from the first 1133 children to have been investigated through this large-scale study. Case 4 was a phenotypically isolated case recruited into an undiagnosed rare disorders sequencing study.
  
  
  RESULTS
  Protein-altering de novo mutations in PURA were identified in four subjects. They include two different frameshifts, one inframe deletion and one missense mutation. PURA encodes Pur-α, a highly conserved multifunctional protein that has an important role in normal postnatal brain development in animal models. The associated human phenotype of de novo heterozygous mutations in this gene is variable, but moderate to severe neurodevelopmental delay and learning disability are common to all. Neonatal hypotonia, early feeding difficulties and seizures, or 'seizure-like' movements, were also common. Additionally, it is suspected that anterior pituitary dysregulation may be within the spectrum of this disorder. Psychomotor developmental outcomes appear variable between patients, and we propose a possible genotype-phenotype correlation, with disruption of Pur repeat III resulting in a more severe phenotype.
  
  
  CONCLUSIONS
  These findings provide definitive evidence for the role of PURA in causing a variable syndrome of neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements and epilepsy in humans, and help clarify the role of PURA in the previously described 5q31.3 microdeletion phenotype.
authors.affiliation: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
authors.forename: David
authors.initials: D
authors.lastname: Hunt
authors.affiliation: The Royal Children's Hospital Department of Neurology, University of Melbourne Department of Paediatrics and the Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia Departments of Integrated Systems Biology and of Pediatrics, School of Medicine and Health Sciences, George Washington University, USA Illumina, Inc., San Diego, California, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Taft
authors.affiliation: Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.affiliation: Department of Radiology, Southampton General Hospital, Southampton, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Gawne-Cain
authors.affiliation: Genetic Medicine, Belfast City Hospital, Belfast, Northern Ireland.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Magee
authors.affiliation: Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Turnpenny
authors.affiliation: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, Hampshire, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Baralle
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D019066:Facies; D005260:Female; D023061:Gene Order; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007859:Learning Disabilities / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C501130:PURA protein, human; D014157:Transcription Factors
keywords: Clinical genetics; Developmental; Epilepsy and seizures; Neurology