Molecular Genetics of von Willebrand Disease in Korean Patients: Novel Variants and Limited Diagnostic Utility of Multiplex Ligation-Dependent Probe Amplification Analyses

초록

Background: von Willebrand disease (VWD), characterized by quantitative or qualitative defects of von Willebrand factor (VWF), is the most common inheritable bleeding disorder. Data regarding the genetic background of VWD in Korean patients is limited. To our knowledge, this is the first comprehensive molecular genetic investigation of Korean patients with VWD. Methods: Twenty-two unrelated patients with VWD were recruited from August 2014 to December 2017 (age range 28 months-64 years; male:female ratio 1.2:1). Fifteen patients had type 1, six had type 2, and one had type 3 VWD. Blood samples were collected for coagulation analyses and molecular genetic analyses from each patient. Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed. In patients without sequence variants, multiplex ligation-dependent probe amplification (MLPA) was performed to detect dosage variants. We adapted the American College of Medical Genetics and Genomics guidelines for variant interpretation and considered variants of uncertain significance, likely pathogenic variants, and pathogenic variants as putative disease-causing variants. Results: VWF variants were identified in 15 patients (68%): 14 patients with a single heterozygous variant and one patient with two heterozygous variants. The variants consisted of 13 missense variants, one small insertion, and one splicing variant. Four variants were novel: p.S764Efs*16, p.C889R, p.C1130Y, and p.W2193C. MLPA analysis in seven patients without reportable variants revealed no dosage variants. Conclusions: This study revealed the spectrum of VWF variants, including novel ones, and limited diagnostic utility of MLPA analyses in Korean patients with VWD.

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