Case: Index Patient (IP), Female, 26 years old; described as from a genetically isolated population (not further specified), consistent with elevated homozygosity rates in that population.
DiseaseAssertion: Type 3 VWD, confirmed by VWF:Ag <4 IU/dL (virtual absence of VWF).
FamilyInfo: NA — no relatives' bleeding history or genotype reported
ParentalGenotype(s): NA (not tested/not reported)
CasePresentingHPOs: HP:0000421 (Epistaxis — frequent nosebleeds), HP:0000132 (Menorrhagia — heavy, prolonged, led to iron-deficiency anemia), HP:0001934 (Persistent bleeding after trauma — bleeding following injury), HP:0012147 (Reduced quantity of VWF; VWF:Ag <4 IU/dL), HP:0030129 (Impaired VWF:RCo-type activity; VWF:GPIbM <4 IU/dL)
CaseHPOFreeText: Easy bruising (no matching HPO code in the approved list); FVIII:C 2.0 IU/dL (nv 70–157); referred to Hemophilia Centre at age 1 for bleeding complications; declined recommended lifelong prophylaxis due to injection discomfort, later underwent prophylaxis with plasma-derived VWF/FVIII concentrates and on-demand treatment (tranexamic acid, oral contraceptives, replacement therapy). Supporting functional evidence from patient-derived endothelial colony-forming cells (ECFCs): virtual absence of VWF mRNA (RQ ~0.04–0.05 vs. 1.00 in healthy controls, across 4 primer/probe sets); VWF secretion into ECFC medium 6.2% ± 0.4% of healthy controls (p<0.0001); near-total absence of Weibel-Palade bodies on immunofluorescence (only 1–3 small WPBs seen in some cells vs. normal stick-shaped WPBs in controls); altered intracellular trafficking of angiopoietin-2 (WPB inflammatory cargo) in the absence of WPBs.
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: Routine testing (Sanger sequencing of coding exons, ~50 bp flanking intronic regions, promoter, 5'/3'-UTR, plus MLPA) was negative — patient was "mutation-negative" prior to this study. Not genome-wide; targeted to VWF only, but comprehensive: this study's NGS covered the entire 176 kb VWF locus (all 52 exons, full intronic regions, promoter) at 30x coverage, going well beyond standard exon+flanking-intron approaches specifically to find deep intronic variants.
GenotypingMethod: Illumina NovaSeq 6000 NGS (2×150 bp reads) of the whole VWF genomic region; variant annotation via Ensembl VEP with SpliceAI, PolyPhen-2, SIFT; splice effect independently confirmed with Neural Network Splicing, ASSP, and MaxEnt/HSF prediction tools. Functional validation via patient-derived ECFCs: RT-qPCR of VWF mRNA (4 primer/probe sets), cDNA sequencing, VWF:Ag ELISA of ECFC secretion, immunofluorescence microscopy, and whole-transcriptome RNA-seq.
PreviouslyPublished: NA — no indication this patient was reported elsewhere; paper explicitly frames this variant/mechanism as a first report.
Gene: VWF
Variant: Novel homozygous deep intronic variant, intron 8, creating a new donor splice site that outcompetes the native donor site, causing inclusion of a 118-bp pseudoexon, frameshift, premature stop codon, and nonsense-mediated decay of the transcript.
HGVS: NM_000552.5:c.997+118T>G (confirmed via ClinGen Allele Registry Community Standard Title; not explicitly stated in the paper's main text, which only gives cDNA/genomic coordinates without a transcript version). Genomic: g.6073501A>C (GRCh38/hg38; note the T>G/A>C discrepancy reflects VWF being transcribed from the minus strand of chr12).
ClinVarID: NA
CAID: CA3275979827
gnomAD: NA