title: Exome sequencing analysis in a pair of monozygotic twins re-evaluates the genetics behind their intellectual disability and reveals a CHD2 mutation.
abstract: BACKGROUND
  Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders.
  
  
  METHODS
  We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype.
  
  
  CONCLUSIONS
  This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pinto
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bianciardi
authors.affiliation: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Imperatore
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Marco
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Furini
authors.affiliation: Child Neurology Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padova, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Suppiej
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: University of Padova, Padova, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ariani
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: alessandra.renieri@unisi.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004200:Diseases in Twins; D059472:Exome; D005145:Face / Q000002:abnormalities; D060005:Genotyping Techniques; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C575189:CHD2 protein, human; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2
keywords: Copy number variants re-evaluation; Epilepsy; Neurodevelopmental disorders; Next generation sequencing