BII:3
Proband: FB_II:3, male age unknown
Family details: parents are unaffected heterozygotes, VWF:Ag on the low end of reference range
Labs: prolonged bleeding time (15min), reduced VWF:Ag (0.09 IU/mL), FVIII:Ag (0.33 IU/mL), FVIII:C (0.21 IU/mL), and VWF:RiCoF (0.04 IU/mL), absent multimers
Genotype: p.Arg273Trp reported as c.1067C>T (MANE transcript is 817C>T)
CAID: CA228829
CII:6
Proband: FC_II:6, male age unknown
FamilyDetails: parents are unaffected hets, first cousins, fathers VWF:Ag at very low end of reference
Labs: prolonged bleeding time (>20min), reduced VWF:Ag (less than 0.01 IU/mL), FVIII:Ag (0.06 IU/mL), FVIII:C (0.09 IU/mL), and VWF:RiCoF (less than 0.01 IU/mL), absent multimers
Genotype: p.Arg273Trp reported as c.1067C>T (MANE transcript is 817C>T)
CAID: CA228829
For p.Val682Leu,
Case#: P5 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: Investigation found that large gene defect was not found in the patient P5's mother and grandmother
CasePresentingHPOs: HP:0003125, HP:0001928, HP:0001892
CaseHPOFreeText: Low FVIII levels (FVIII:C levels were significantly decreased compared to the WT (13.4% ± 0.8, P < 0.01); FVIII:Ag levels were normal both in the conditioned media and cell lysate (respectively 90.7% ± 6.3 and 109.0% ± 9.5)), abnormal blood coagulation, mild bleeding tendency, haematoma
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.
Gene: F8
Variant: NM_000132.4:c.2044G>C
CAID: CA414909252
gnomAD: Absent/Not Reported
A 30‐year‐old male patient
Case#: Patient B, Male, Age 30, Chinese
Disease Assertion: VWD3
FamilyInfo: Consanguineous marriage between parents. Parents had 2 daughters and a son. One daughter died (1 year old) due to bleeding disorder. Mother's VWF:Ag 58% and VWF:RCo 36%. Family pedigree in Figure 2 (a). Both parents were heterozygous carriers of the variant.
Parental Genotype: Both Heterozygous
CasePresentingHPOs: HP:0003645
(Prolonged partial thromboplastin time)
CaseHPOFreeText: Hematoma in the lower extremity, VWF:Ag: 0.5%, VWF:RCo: 0.1%, FVIII:C 1.2%, APTT: 72.0 s
CaseNotHPOs:
CaseNotHPOFreeText: PT: 13.6 s, TT: 14.9s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8, F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4:c.6450C>A
ClinVar: N/A
CAID: CA383491381 CAID
gnomAD:N/A
Quantitative 3D microscopy highlights altered von Willebrand factor α‐granule storage in patients with von Willebrand disease with distinct pathogenic mechanisms
PMID: 34532631
Notes: Homozygous instance of an otherwise type 2 variant, Cys1190Arg
Case#: 13001, Age 61, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient was the only member of Family# 1301.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 27, VWF:Ag: 11, VWF:RCo: 9.7, FVIII:C: 36, VWF:CB: 12
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.7985A>G
ClinVar: N/A
CAID: CA383487641 CAID
gnomAD: N/A
Case#: 27024, Age 56, Female, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#2713.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:5.3, VWF:RCo:6, FVIII:C:38, VWF:CB:4.2
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 3
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G
ClinVar: 100264 ClinVar
CAID: CA228414 CAID
gnomAD: N/A
Current age 26 years
Disease: Myopathic Ehlers-Danlos Syndrome (mEDS)
Patient(s): 47 yo male, japanese descent
Variant: COL12A1 NM_004370.6: c.395-1G>A (Homozygous variant, at splice acceptor site in exon 6, causes in-frame skipping)(located in the genomic region encoding the first von Willebrand factor A domain)
Family: consanguineous parents with no related features of mEDS, healthy older brother
Phenotypes (Childhood): hypotonia, weak spontaneous movements, scoliosis, torticollis, soft plams, undescended testes, motor developmental delay, slender build, triangular face, short palpebral fissures, small nose, small mouth, large ears, bilateral knee dislocations, short stature.
Phenotypes (Adulthood): short stature, high palate, hypermobile small joints, deformed cervical spine, brachycephaly, bilateral long deformed 5th finger, severe scoliosis post surgical fixation, asymmetric pelvis
Classification: sequencing panel found the variant and it was confirmed through sanger sequencing.
According to ClinGenSVI recommendation: PVS1_Strong
Applicable criteria:
1) the one at a GT-AG 1,2 splice site
2) the one exerting exon skipping or use of a crypic splice site that preserved the reading frame.
3) the one at a truncated/altered region critical to protein function; was classified as PM3_Supporting (homozygous)
Variant not registered in gnomAD (PM2_Supporting)
Partial defect of first vWA in collagen XII judged as PS3
Disease: Von Willebrand Disease (VWD)
Patient(s): Found in 2 families
Variant: VWF NM_000552.5: c.2311A>G, p.(M771V Homozygous variant in exon 18 (VWF D' domain; 8 residues down from proteolytic VWFpp furin cleavage site)
Family: In family 1 there are 4 homozygous patients (2 male and 2 female), and one heterozygous patient (1 female). The affected females are denoted as person 1 and person 4 and the affected males are person 2 and person 3. There are three WT family members (1 female and 2 male), grandparents of these members are of unknown genotype including a daughter of an affected female and a WT male. Note here that in the family a p.R2663P variant has co-segregated with the above-mentioned variant but is not suspected to be the pathogenic driver of resulting bleeding tendency.
In family 2 the parents of the homozygous affected male are of unknown genotype. The affected male is denoted as person 7.
Phenotypes: Person 1- nose bleed, skin bleed, GI bleeding, oral cavity bleeds, Menorrhagia, muscle bleeding, and joint bleeding. Receives on-demand treatment for bleeding.
Person 2-Nose bleed, skin bleed, bleeding from small wounds, oral cavity bleeds, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment, reduced to on-demand treatment after a few years.
Person 3-Nose bleed, skin bleed, oral cavity bleeds, bleeding after tooth extraction, muscle bleeding. Receives on-demand treatment for bleeding phenotype.
Person 4- Nose bleed, bleeding from small wounds, oral cavity bleed, bleeding after tooth extraction, joint bleeding. Received prophylactic treatment that was increased after her menarche.
Person 7- Nose bleed, oral cavity bleeds, bleeding after surgery or trauma, joint bleeding. Previously on prophylaxis, now managing bleeding with on-demand treatment.
Note that both the p.R2663P co-segregated variant and p.M771V variant are reported in NCBI dbSNP database but functional effect not yet established.
NGS confirmed the genotype of all study participants.
T and T
t and t, not T and T, because recessive