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The γ-glutamyl carboxylase encoded by GGCX catalyzes the post-translational γ-carboxylation of vitamin K-dependent proteins essential for coagulation and extracellular matrix mineralization. Loss‐of‐function variants in GGCX underlie hereditary combined vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), manifesting with bleeding diathesis and skin hyperlaxity classified as body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency.
Inheritance is autosomal recessive. Four unrelated probands in two distinct families with biallelic GGCX variants have been reported, including compound heterozygosity for a splice‐site change and a missense substitution, and uniparental disomy, confirming loss‐of‐function as the disease mechanism (4 probands total; 2 families) (PMID:15287948, PMID:27681307).
ClinGen classification: Moderate
a. 4 probands with molecularly confirmed biallelic GGCX variants; autosomal recessive inheritance; concordant functional data.
VKCFD1 arises from homozygous or compound heterozygous GGCX variants. Reported variant classes include: 1 splice‐site mutation (c.215-1G>T) and multiple missense changes. Recurrent alleles or founder variants have not been observed. No additional segregation beyond probands has been documented.
Representative variant: c.1454G>C (p.Arg485Pro) (PMID:15287948).
Genetic evidence tier: Moderate (“3 probands with compound heterozygous variants; AR inheritance; functional concordance”).
Biochemical and cellular assays demonstrate that missense variants such as p.Arg485Pro impair γ-glutamyl carboxylase activity, leading to defective carboxylation of coagulation factors and matrix Gla protein. Rescue experiments with vitamin K only partially normalize activity, consistent with in vivo bleeding and cutaneous phenotypes. Complementary studies of Δ2GGCX splice‐isoform overexpression via uniparental disomy models confirm that loss of full‐length GGCX disrupts both hepatic and extra‐hepatic vitamin K-dependent proteins.
Functional evidence tier: Moderate (“Multiple in vitro assays and UPD model confirm loss of GGCX function; partial rescue with vitamin K”).
Biallelic GGCX loss‐of‐function variants cause an autosomal recessive syndrome of combined coagulation factor deficiency with marked skin hyperlaxity. Genetic findings are supported by concordant functional assays demonstrating impaired enzyme activity. This association informs molecular diagnosis, guides vitamin K supplementation strategies, and facilitates genetic counseling for VKCFD1 patients with cutaneous manifestations.
Key take‐home: AR GGCX mutations should be considered in patients with unexplained bleeding and skin hyperlaxity to enable targeted therapy and family screening.
Gene–Disease AssociationModerate4 probands in 2 families with biallelic GGCX variants; autosomal recessive inheritance; concordant functional data Genetic EvidenceModerate3 probands with compound heterozygous variants; AR inheritance; functional concordance Functional EvidenceModerateMultiple in vitro assays and UPD model confirm loss of GGCX function; partial rescue with vitamin K |