title: Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit.
  
  
  
  Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency.
  
  
  
  Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI.
  
  
  
  Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.
authors: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK; Highly Specialised Service for Severe, Complex and Atypical OI, UK. Electronic address: meena.balasubramanian@nhs.net.
authors: M
authors: M
authors: Balasubramanian
authors: NE Thames Clinical Genetics Service, Great Ormond Street Hospital, UK.
authors: J
authors: J
authors: Hurst
authors: Sheffield RNAi Screening Facility, Department of Biomedical Sciences, University of Sheffield, UK.
authors: S
authors: S
authors: Brown
authors: Highly Specialised Service for Severe, Complex and Atypical OI, UK; Academic Unit of Child Health, University of Sheffield, UK.
authors: N J
authors: NJ
authors: Bishop
authors: Highly Specialised Service for Severe, Complex and Atypical OI, UK.
authors: P
authors: P
authors: Arundel
authors: Highly Specialised Service for Severe, Complex and Atypical OI, UK.
authors: C
authors: C
authors: DeVile
authors: Academic Unit of Child Health, University of Sheffield, UK; Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
authors: R C
authors: RC
authors: Pollitt
authors: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK; Department of Biosciences and Chemistry, Sheffield Hallam University, UK.
authors: L
authors: L
authors: Crooks
authors: MRC Human Genetics Unit, IGMM, University of Edinburgh, UK.
authors: D
authors: D
authors: Longman
authors: MRC Human Genetics Unit, IGMM, University of Edinburgh, UK.
authors: J F
authors: JF
authors: Caceres
authors: Department of Paediatric Immunology, Sheffield Children's NHS Foundation Trust, UK.
authors: F
authors: F
authors: Shackley
authors: Department of Paediatric Hepatology, Sheffield Children's NHS Foundation Trust, UK.
authors: S
authors: S
authors: Connolly
authors: Department of Paediatric Haematology, Sheffield Children's NHS Foundation Trust, UK.
authors: J H
authors: JH
authors: Payne
authors: Highly Specialised Service for Severe, Complex and Atypical OI, UK; Academic Unit of Child Health, University of Sheffield, UK.
authors: A C
authors: AC
authors: Offiah
authors: Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, UK.
authors: D
authors: D
authors: Hughes
authors: DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
authors: M J
authors: MJ
authors: Parker
authors: Centre for Computational Biology, Sheffield Institute of Translational Neuroscience, University of Sheffield, UK.
authors: W
authors: W
authors: Hide
authors: Mellanby Bone Research Centre, Department of Oncology & Metabolism, University of Sheffield, UK.
authors: T M
authors: TM
authors: Skerry
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005347:Fibroblasts / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics*; D000072417:Protein Domains; D012867:Skin / Q000473:pathology / Q000648:ultrastructure
chemical_list: C117339:NBAS protein, human; D009363:Neoplasm Proteins
keywords: Bone; Collagen expression; Fragility; NBAS; Nonsense mediated decay (NMD); Osteogenesis imperfecta; Secretory pathway