Very Low Vitamin D in a Patient With a Novel Pathogenic Variant in the Gene That Encodes Vitamin D-Binding Protein.

Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as roup-specific omponent or Gc-globulin. DBP, encoded by the gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures, and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of revealed a homozygous pathogenic variant affecting a canonical splice site (c0.702-1G > A). These findings indicate that loss of function variants in that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.