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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s12881-016-0344-9) contains supplementary material, which is available to authorized users.

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