title: Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.
abstract: BACKGROUND
  Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions.
  
  
  OBJECTIVE
  The objective of the study was to find the genetic etiology of a novel presentation of MPD.
  
  
  METHODS
  The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model.
  
  
  METHODS
  Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities.
  
  
  METHODS
  NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied.
  
  
  RESULTS
  From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype.
  
  
  CONCLUSIONS
  We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients.
authors.affiliation: Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. andrew.dauber@childrens.harvard.edu
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Lafranchi
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Maliga
authors.forename: Julian C
authors.initials: JC
authors.lastname: Lui
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Moon
authors.forename: Cailin
authors.initials: C
authors.lastname: McDeed
authors.forename: Katrin
authors.initials: K
authors.lastname: Henke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zonana
authors.forename: Garrett A
authors.initials: GA
authors.lastname: Kingman
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baron
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Harris
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
mesh_terms: D000293:Adolescent; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; C512806:NIN protein, human; D009687:Nuclear Proteins