title: Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.
abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.
  
  
  
  Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.
  
  
  
  Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.
  
  
  
  The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.
authors.affiliation: Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.|Current address: Department of Neurosciences, University of California San Diego, San Diego, California, USA.
authors.forename: Samin A
authors.initials: SA
authors.lastname: Sajan
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
authors.forename: James R
authors.identifier: 0000-0001-9907-9246
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Glaze
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Steven A
authors.identifier: 0000-0003-3844-0792
authors.initials: SA
authors.lastname: Skinner
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Fran
authors.initials: F
authors.lastname: Annese
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Lane
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Percy
authors.affiliation: Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Current address: Department of Neurosciences, University of California San Diego, San Diego, California, USA.
authors.forename: Jeffrey L
authors.identifier: 0000-0002-5628-5872
authors.initials: JL
authors.lastname: Neul
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology; D000073359:Exome Sequencing
chemical_list: D002843:Chromatin; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human