title: Expanding Genetic and Functional Diagnoses of IGF1R Haploinsufficiencies.
abstract: BACKGROUND
  The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth.
  
  
  METHODS
  Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients.
  
  
  RESULTS
  Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a ∼50% reduction in IGF1R availability associated with the haploinsufficiency state.
  
  
  CONCLUSIONS
  In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy.
authors.affiliation: Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.
authors.forename: Paula
authors.initials: P
authors.lastname: Ocaranza
authors.affiliation: Pediatric Endocrinology, Children's Hospital of Michigan, Detroit, Michigan, USA.
authors.forename: Marjorie C
authors.initials: MC
authors.lastname: Golekoh
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Shayne F
authors.initials: SF
authors.lastname: Andrew
authors.affiliation: Division of Endocrinology, Boston Children's Hospital and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Guo
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Children's National Health System, Washington, District of Columbia, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kaplowitz
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Saal
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.affiliation: Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cassorla
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Philippe F
authors.initials: PF
authors.lastname: Backeljauw
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
mesh_terms: D002648:Child; D059472:Exome; D005260:Female; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D057895:Haploinsufficiency; D006801:Humans; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*
chemical_list: C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1
keywords: FACS analysis; IGF1R copy number variants; Short stature; Whole exome sequencing