Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype

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  • Job, Florian
    • Other Affiliation: Martin Luther University Halle-Wittenberg
  • Mizumoto, Shuji
    • Other Affiliation: Meijo University
  • Smith, Laurie
    • Affiliation: School of Medicine, Department of Pediatrics
  • Couser, Natario
    • Affiliation: School of Medicine, Department of Pediatrics
  • Brazil, Ashley
    • Other Affiliation: Cincinnati Children’s Hospital Medical Center
  • Saal, Howard
    • Other Affiliation: Cincinnati Children’s Hospital Medical Center
  • Patterson, Melanie
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Gibson, Margaret I
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Soden, Sarah
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Miller, Neil
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Thiffault, Isabelle
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Saunders, Carol
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
  • Yamada, Shuhei
    • Other Affiliation: Meijo University
  • Hoffmann, Katrin
    • Other Affiliation: Martin Luther University Halle-Wittenberg
  • Sugahara, Kazuyuki
    • Other Affiliation: Meijo University
  • Farrow, Emily
    • Other Affiliation: Children’s Mercy Hospitals and Clinics
Abstract
  • Background A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals. Case presentation In this study, a 4-year-old patient with a severe phenotype of osteoporosis, hypotonia, joint laxity, fractures, scoliosis, biscuspid aortic valve and myopia was referred for next generation sequencing after extensive negative clinical testing. Whole exome sequencing was performed on the proband and his unaffected parents to identify the molecular basis of his disease. Sequencing revealed compound heterozygous variants in B3GAT3: c.1A > G (p.Met1?) and c.671 T > A (p.L224Q). Clinical and in vitro functional studies were then completed to verify the pathogenicity of the genotype and further characterize the functional basis of the patient’s disease demonstrating the patient had a decrease both in the protein level of B3GAT3 and in the glucuronyltransferase activity when compared to control samples. Independent in vitro assessment of each variant confirmed the B3GAT3: c.1A > G (p.Met1?) variant is functionally null and the c.671 T > A (p.L224Q) missense variant has significantly reduced glucuronyltransferase activity (~3% of control). Conclusions This is the first report of a patient with compound heterozygosity for a null variant in trans with a missense in B3GAT3 resulting in a severe phenotype, expanding both the genotypic and phenotypic spectrum of B3GAT3-related disease.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • The Author(s).
Journal title
  • BMC Medical Genetics
Journal volume
  • 17
Journal issue
  • 1
Language
  • English
Bibliographic citation
  • BMC Medical Genetics. 2016 Nov 21;17(1):86
Publisher
  • BioMed Central

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