Molecular Genetics of von Willebrand Disease in Korean Patients: Novel Variants and Limited Diagnostic Utility of Multiplex Ligation-Dependent Probe Amplification Analyses
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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.
Abstract
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.
참고문헌 (31)
- Rodeghiero F, "Epidemiological investigation of the prevalence of von Willebrand’s disease", Blood, 69, pp.454~459 (1987)
- Goodeve AC, "The genetic basis of von Willebrand disease", Blood Rev, 24, pp.123~134 (2010)
- Mancuso DJ, "Structure of the gene for human von Willebrand factor", J Biol Chem, 264, pp.19514~19527 (1989)
- Zhou YF, "Sequence and structure relationships within von Willebrand factor", Blood, 120, pp.449~458 (2012)
- Sadler JE, "Update on the pathophysiology and classification of von Willebrand disease : a report of the Subcommittee on von Willebrand Factor", J Thromb Haemost, 4, pp.2103~2114 (2006)
- Schneppenheim R, "The pathophysiology of von Willebrand disease: therapeutic implications", Thromb Res, 128(1), pp.S3~S7 (2011)
- Baronciani L, "Molecular diagnosis of von Willebrand disease", Haemophilia, 23, pp.188~197 (2017)
- Kim HJ, "Mutation spectrum and inhibitor risk in 100 Korean patients with severe haemophilia A", Haemophilia, 18, pp.1008~1013 (2012)
- Yadegari H, "Large deletions identified in patients with von Willebrand disease using multiple ligation-dependent probe amplification", J Thromb Haemost, 9, pp.1083~1086 (2011)
- Wang QY, "Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes", J Thromb Haemost, 11, pp.261~269 (2013)
- 송재우, "한국 von Willebrand병 환자의 von Willebrand 인자 유전자 돌연변이 조사", Annals of Laboratory Medicine, 27(3), pp.169~176 (2007), 대한진단검사의학회
- Rodeghiero F, "The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease : an international, multicenter study", J Thromb Haemost, 3, pp.2619~2626 (2005)
- Corrales I, "Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene", Thromb Haemost, 101, pp.570~576 (2009)
- den Dunnen JT, "HGVS Recommendations for the Description of Sequence Variants : 2016 Update", Hum Mutat, 37, pp.564~569 (2016)
- Cabrera N, "First application of MLPA method in severe von Willebrand disease. Confirmation of a new large VWF gene deletion and identification of heterozygous carriers", Br J Haematol, 152, pp.240~242 (2011)
- Richards S, "Standards and guidelines for the interpretation of sequence variants : a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
- Mikhail S, "An update on type 2B von Willebrand disease", Expert Rev Hematol, 7, pp.217~231 (2014)
- Yadegari H, "Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease(VWD)types in a cohort of VWD patients", Thromb Haemost, 108, pp.662~671 (2012)
- Eikenboom J, "Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD", J Thromb Haemost, 4, pp.774~782 (2006)
- James PD, "Genetic linkage and association analysis in type 1 von Willebrand disease : results from the Canadian type 1 VWD study", J Thromb Haemost, 4, pp.783~792 (2006)
- Meyer D, "Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand disease", Thromb Haemost, 78, pp.451~456 (1997)
- Casonato A, "Identifying carriers of type 2N von Willebrand disease : procedures and significance", Clin Appl Thromb Hemost, 13, pp.194~200 (2007)
- Choi H, "Shear-induced disulfide bond formation regulates adhesion activity of von Willebrand factor", J Biol Chem, 282, pp.35604~35611 (2007)
- Shapiro SE, "The von Willebrand factor predicted unpaired cysteines are essential for secretion", J Thromb Haemost, 12, pp.246~254 (2014)
- Eikenboom JC, "Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor", Blood, 88, pp.2433~2441 (1996)
- Goodeve A, "Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand disease(MCMDM-1VWD)", Blood, 109, pp.112~121 (2007)
- Eikenboom JC, "Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin", Thromb Haemost, 79, pp.709~717 (1998)
- Tjernberg P, "Dimerization and multimerization defects of von Willebrand factor due to mutated cysteine residues", J Thromb Haemost, 2, pp.257~265 (2004)
- Casari C, "Clearance of von Willebrand factor", J Thromb Haemost, 11(S1), pp.202~211 (2013)
- Choung HS, "Inherited protein S deficiency as a result of a large duplication mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification", J Thromb Haemost, 6, pp.1430~1432 (2008)
- Kim HJ, "Heterogeneous lengths of copy number mutations in human coagulopathy revealed by genome-wide high-density SNP array", Haematologica, 97, pp.304~309 (2012)