Founder mutation Arg485Pro led to recurrent compound heterozygous GGCX genotypes in two German patients with VKCFD...

Area of Science:

• Genetics
• Hematology
• Biochemistry

Background:

• Congenital combined deficiency of vitamin-K-dependent coagulation factors (VKCFD) is a rare inherited bleeding disorder.
• It results from mutations in genes responsible for vitamin K metabolism, specifically the gamma-glutamyl carboxylase (GGCX) gene (VKCFD type 1) or the vitamin K epoxide reductase gene (VKCFD type 2).

Observation:

• Four distinct GGCX gene mutations have been documented in VKCFD type 1 patients.
• This report details a fourth patient with VKCFD type 1, presenting compound heterozygous missense mutations in the GGCX gene: His404Pro and Arg485Pro.

Findings:

• The His404Pro mutation is novel, while Arg485Pro was previously identified in another German patient.
• Haplotype analysis indicates that Arg485Pro is a founder mutation, suggesting its presence at a low frequency within the German population.
• This founder effect likely explains the German origin of the two known compound heterozygous VKCFD type 1 patients.

Implications:

• The identification of novel GGCX mutations expands the known mutational spectrum for VKCFD type 1.
• Understanding the genetic basis and population frequency of these mutations is crucial for diagnosis and genetic counseling.
• The discovery of a founder mutation in the German population highlights the importance of population-specific genetic studies in rare diseases.