Uniparental disomy causes deficiencies of vitamin K‐dependent proteins

Essentials Vitamin K‐dependent coagulant factor deficiency (VKCFD) is a rare autosomal recessive disorder. We describe a case of inherited VKCFD due to uniparental disomy. The homozygous mutation caused the absence of GGCX isoform 1 and overexpression of Δ2GGCX. Hepatic and non‐hepatic vitamin K‐dependent proteins must be assayed to monitor VKCFD treatment.Summary Background Inherited deficiency of all vitamin K‐dependent coagulant factors ( VKCFD ) is a rare autosomal recessive disorder caused by mutations in the γ‐glutamyl carboxylase gene ( GGCX ) or the vitamin K epoxide reductase gene ( VKORC 1 ), with great heterogeneity in terms of both clinical presentation and response to treatment. Objective To characterize the molecular basis of VKCFD in a Spanish family. Methods and Results Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband. Uniparental disomy ( UPD ) of chromosome 2 caused homozygosity of a mutation (c.44‐1G>A) resulting in aberrant GGCX splicing. This change contributed to absent expression of the m RNA coding for the full‐length protein, and to four‐fold overexpression of the smaller m RNA isoform lacking exon 2 (Δ2 GGCX ). Δ2 GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K 1 supplementation; and (ii) a mild non‐bleeding phenotype. Conclusions Our study identifies a new autosomal disease, VKCFD 1, caused by UPD . These data suggest that the Δ2 GGCX isoform may retain enzymatic activity, and strongly encourage the evaluation of both hepatic and non‐hepatic vitamin K‐dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.