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
Proband: F4_AM, 27yo (at report) female
Phenotypes: HP:0030134, HP:0003010, HP:0030129
Family: Both parents carry the variant. All het carriers were classified type 1
Labs: FVIII 0.02 IU/mL, VWF 0.03 IU/mL (below detection threshold)
Variant: NM_000552.5:c.4975C>T
CAID: CA114141
Disease: Von-willebrand Disorder Type 3
Patient: 26 yo, female
Variant: VWF NM_000552.5 c:997+118 T>G g.(6073501 A>C), homozygous, intronic
Phenotypes: No detectable VWF in plasma, early onset bleeding complications, epistaxis, easy bruising, bleeding following injury, menorrhagia, iron-deficient anemia
Note: underwent prophylaxis replacement therapy, on-demand antihemorrhagic treatments, oral contraceptives, and replacement therapy.
Family: not mentioned
Predictions:
VEP SpliceAI tool predicted variant likely deleterious (delta score 0.95)
Used Polyphen-2 and SIFT which determined pathogenic likelihood.
Neural Network Splicing, Alternative Splice Site Predictor, plug-in MaxEnt(For 5' donor site) of Human Splicing Finder all concur this variant can create a new donor splice site in intron 8. Contains premature stop codon and susceptible to NMD.
Functional work:
qRT-PCR performed to identify levels of VWF in IP-derived endothelial cells.
histochemical immunostaining for IP-derived endothelial cells confirm no VWF production, only a residual amount present. Suggests leaky mutation.
performed RNA sequencing to assess co-regulated gene networks