Phenotypic and genotypic characterization of hereditary factor X deficiency (FXD) identified 11 novel genetic mutations not previously associated with the disease, according to findings published in Blood Coagulation and Fibrinolysis.

Hereditary FXD is a rare autosomal recessive bleeding disorder. Mutations in the F10 gene located on chromosome 13q34-ter cause the disease, and 149 mutations have previously been identified.

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In 3 open label, phase 3 clinical trials, patients with mild, moderate, or severe FXD received plasma-derived factor X concentrate as routine prophylaxis, to treat bleeds, or for treatment during or following surgery. Researchers performed F10 genotyping on patients in 2 of the studies and collected genotype data at screening in the third. They compared identified F10 mutations with the Human Gene Mutation Database to determine novelty.

Combined genotype data enabled assessment of the number, type, and novelty of the identified F10 mutations, with genotype data available for 24 of 27 patients with FXD. Of these patients, 2 had mild FXD, 2 had moderate FXD, and 20 had severe FXD.

The researchers identified 22 separate mutations: 15 missense mutations, 2 deletions, 4 splice-site mutations, and 1 nonsense mutation. A total of 16 patients harbored homozygous mutations; the 8 remaining patients had compound heterozygous mutations.

Researchers identified 11 novel mutations in 7 patients. All 11 mutations occurred as compound heterozygous mutations. Of these, 6 were missense mutations, 3 were splice-site mutations, 1 was an exon deletion, and 1 was a nonsense mutation.

Additional in silico analyses indicated these mutations’ putative pathogenic involvement in the etiology of FXD.

“The identification of 11 novel mutations provides a substantial contribution to the mutations known to cause FXD,” the authors wrote. “As most mutations occurred in only one or two individuals, we were unable to draw definitive conclusions regarding genotype-phenotype associations.” The authors concluded that larger studies in more patients are needed to better characterize the contributions of individual mutations to the disease.

Reference

1.     Mitchell M, Gattens M, Kavakli K, et al. Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency [published online January 1, 2019]. Blood Coagul Fibrinolysis. doi: 10.1097/MBC.0000000000000787