Case: Patient B, male, 11 years old at WIL-29 study entry; ethnicity not reported.

DiseaseAssertion: VWD3. The patient was initially suspected to have VWD2A based on the family history but was reclassified as VWD3 after next-generation sequencing.

FamilyInfo: Patient B and Patient A are brothers from a consanguineous family. Both parents were diagnosed with VWD. Figure 2 shows both parents as heterozygous and Patient A and Patient B as homozygous for the familial VWF variant. The pedigree also includes another brother affected with VWD whose genetic testing was underway and a sister whose VWD diagnosis and genetic testing were pending.

ParentalGenotype: Both parents were heterozygous for the familial VWF variant, as shown in Figure 2.

CasePresentingHPOs: HP:0000421, HP:0030129 (Epistaxis, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1%; historical VWF:Ag not measured. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 16 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, maximum VWF:RCo 65 IU/dL and in vivo recovery 1.02 kg/dL. VWF inhibitors were confirmed present at WIL-31 study entry; no VWF inhibitor was detectable at the 12-month visit.

CaseNotHPOs: NA

CaseNotHPOFreeText: No anaphylactic reactions or severe treatment-related adverse events were reported.

CasePreviousTesting: Diagnosed with VWD shortly after birth and initially suspected to have VWD2A based on family history. Historical VWF activity testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. Historical VWF antigen was not measured. No earlier molecular genetic testing was reported.

GenotypingMethod: Next-generation sequencing performed in Bonn, Germany. Additional technical details regarding the sequencing assay or panel were not provided.

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro, homozygous

HGVS: NM_000552.5:c.4094T>C (p.Leu1365Pro)

ClinVar: 2438545

CAID: NA

gnomAD: Absent (not reported in gnomAD; 0/251040 control chromosomes)

Case: IP #23 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1/M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 14

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro

HGVS:

ClinVarID: 2438545

CAID:

gnomAD: absent