Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

Song, Jaewoo; Choi, Jong Rak; Song, Kyung Soon

doi:10.3343/kjlm.2007.27.3.169

Cited by 4 publications

(6 citation statements)

References 32 publications

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“…We investigated molecular defects of VWF in 22 unrelated Korean patients with VWD recruited from multiple institutions in Korea with a nationwide distribution. The patients consisted of 15 type 1 (68%), six type 2 (27%), and one type 3 (5%), which is largely compatible with the distribution in previous studies in western countries and Korea [1117]. Song, et al [11] screened exons 12, 14, 16, 18, 19, 20, 24, 26, 27, 28, and 52 in Korean patients with VWD.…”

Section: Discussionsupporting

confidence: 81%

“…The patients consisted of 15 type 1 (68%), six type 2 (27%), and one type 3 (5%), which is largely compatible with the distribution in previous studies in western countries and Korea [1117]. Song, et al [11] screened exons 12, 14, 16, 18, 19, 20, 24, 26, 27, 28, and 52 in Korean patients with VWD. They reported variant detection rates of 11%, 30%, and 0% for type 1, type 2, and type 3 VWD, respectively.…”

Section: Discussionsupporting

confidence: 81%

“…Recent studies on population-based sequencing data have demonstrated considerable ethnic diversity in the coding sequence of VWF (http://exac.broadinstitute.org, last updated in August 2016, http://evs.gs.washington.edu/EVS, last updated in May 2015) [10]. So far, only Song, et al [11] have examined the genetic background of VWD in Korean patients. They performed direct sequencing of limited exons in VWF , focusing on locations containing known variants.…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Yoo

et al. 2019

Ann Lab Med

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Backgroundvon 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.MethodsTwenty-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.ResultsVWF 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.ConclusionsThis 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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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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

Kim

Yoo

et al. 2019

Ann Lab Med

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“…As a result, the presence of vWD with a combination of types 1 and 2A was confirmed in the patient, indicating that he was a compound heterozygote: c.2574C > G (p.Cys858Trp) from his father and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (Figure 1). The former nonsynonymous variant has been previously described in vWD type 1, 14,15 whereas the latter synonymous variant has been previously confirmed to result in exon 26 skipping in vWD type 2A. 16 In addition to previously described combined heterozygous variants of VWF, c.822+6G > A in TBXAS1 (heterozygote) and c.12161A > T, p.Tyr4054Phe in LRP1 (homozygote) were found in the index patient.…”

Section: Case Descriptionmentioning

confidence: 66%

“…20 In this study, all of the patient's immediate family members were suspected to have vWD, and as the inheritance pattern of vWD can be unpredictable, genetic testing was performed for confirmation of the disease. Genetic analysis revealed that the patient possessed not only a previously known variant of type 1 vWD, 14,15 but also a variant known in type 2A vWD, 16 which is a highly unique pattern of vWD. This report suggests that the clinical diagnosis of vWD subtype without genetic confirmation may result in an inaccurate diagnosis.…”

Section: Discussionmentioning

confidence: 98%

A case of inherited type 1 and type 2A von Willebrand disease confirmed by diagnostic exome sequencing

Shim

Park

Jung

et al. 2018

Pediatric Blood & Cancer

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A 10-year-old male and his family members visited a pediatric hematology clinic due to coagulopathy. Laboratory tests indicated von Willebrand disease (vWD) in all the family members. We conducted diagnostic exome sequencing for confirmation. The patient was confirmed to be a compound heterozygote for vWD: c.2574C > G (p.Cys858Trp) from his father (known variant of vWD type 1) and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (variant known to result in exon 26 skipping in vWD type 2A). He was managed with factor VIII and von Willebrand factor complex concentrate during palatoplasty due to bleeding despite pre-operative desmopressin injection. The operation was completed successfully.

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A Case of Type 2N von Willebrand Disease with Homozygous R816W Mutation of the VWF Gene in a Nepalese Woman

et al. 2008

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Type 2N von Willebrand disease (vWD) can be confused with hemophilia A due to decreased factor VIII levels and a bleeding tendency, and differential diagnosis is of importance for providing the optimal treatment and genetic counseling. For the accurate diagnosis of type 2N vWD, von Willebrand Factor (vWF) function tests, multimer assay and gene mutation analysis are needed. The patient was a 38-yr-old Nepalese woman with a history of bleeding manifestations from childhood, such as hemarthrosis, intramuscular hematoma, and menorrhagia. Family history revealed that her mother and elder brothers also had bleeding manifestations from childhood. When she had a laparotomy in 1991, she was diagnosed as hemophilia A with factor VIII level of 3.6% and was transfused with whole blood, factor VIII and cryoprecipitates. In June 2007, she was admitted to our hospital for further evaluation of bleeding tendency. Blood tests revealed normal CBC; bleeding time, 2 min; PT, 14.9 sec (11-14 sec); aPTT, 51.2 sec (24-38 sec); and factor VIII, 4.9% (50-150%). The prolonged aPTT was corrected by 1:1 mixing test to the levels of 106% and 84%, respectively, before and after 2 hr-incubation at 37°C. No abnormalities were found in the vWF antigen level (71.3%), ristocetin cofactor assay (130.4%), and multimer assay. Direct DNA sequencing of the VWF gene revealed homozygous missense mutation located in exon 19, c.2446C>T (p.Arg816Trp), confirming the diagnosis of type 2N vWD. (Korean J Lab Med 2008;28:258-61)

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Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

Cited by 4 publications

References 32 publications

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

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

A case of inherited type 1 and type 2A von Willebrand disease confirmed by diagnostic exome sequencing

A Case of Type 2N von Willebrand Disease with Homozygous R816W Mutation of the VWF Gene in a Nepalese Woman

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