title: Identification of an HMGB3 frameshift mutation in a family with an X-linked colobomatous microphthalmia syndrome using whole-genome and X-exome sequencing.
abstract: OBJECTIVE
  Microphthalmias are rare disorders whose genetic bases are not fully understood. HMGB3 is a new candidate gene for X-linked forms of this disease.
  
  
  OBJECTIVE
  To identify the causative gene in a pedigree with an X-linked colobomatous microphthalmos phenotype.
  
  
  METHODS
  Whole-genome sequencing and chromosome X-exome-targeted sequencing were performed at the High Throughput Sequencing Laboratory of the Genetic Resources Core Facility at the Johns Hopkins University School of Medicine on the DNA of the male proband and informatically filtered to identify rare variants. Polymerase chain reaction and Sanger sequencing were used to confirm the variant in the proband and the carrier status of his mother. Thirteen unrelated male patients with a similar phenotype were also screened.
  
  
  METHODS
  Whole-genome and X-exome sequencing to identify a frameshift variant in HMGB3.
  
  
  RESULTS
  A 2-base pair frameshift insertion (c.477_478insTA, coding for p.Lys161Ilefs*54) in the HGMB3 gene was found in the proband and his carrier mother but not in the unrelated patients. The mutation, confirmed by 3 orthogonal methods, alters an evolutionarily conserved region of the HMGB3 protein from a negatively charged polyglutamic acid tract to a positively charged arginine-rich motif that is likely to interfere with normal protein function.
  
  
  CONCLUSIONS
  In this family, microphthalmia, microcephaly, intellectual disability, and short stature are associated with a mutation on the X chromosome in the HMGB3 gene. HMGB3 should be considered when performing genetic studies of patients with similar phenotypes.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David W
authors.initials: DW
authors.lastname: Mohr
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kasch
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Barton
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pittiglio
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Roxann
authors.initials: R
authors.lastname: Ingersoll
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Craig
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Marosy
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: The Jackson Laboratory, Center for Human Genetics, Bar Harbor, Maine.
authors.forename: William C
authors.initials: WC
authors.lastname: Bromley
authors.affiliation: The Jackson Laboratory, Center for Human Genetics, Bar Harbor, Maine.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Roderick
authors.affiliation: CHU Toulouse, Service de Génétique Médicale, Hôpital Purpan, Université Paul-Sabatier Toulouse III, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.affiliation: CHU Toulouse, Service de Génétique Médicale, Hôpital Purpan, Université Paul-Sabatier Toulouse III, Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Shreya S
authors.initials: SS
authors.lastname: Prabhu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland4Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
mesh_terms: D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D003103:Coloboma / Q000235:genetics*; D059472:Exome / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics; D025765:HMGB3 Protein / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008850:Microphthalmos / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D025765:HMGB3 Protein