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Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)

Anne Goodeve, Jeroen Eikenboom, Giancarlo Castaman, Francesco Rodeghiero, Augusto B. Federici, Javier Batlle, Dominique Meyer, Claudine Mazurier, Jenny Goudemand, Reinhard Schneppenheim, Ulrich Budde, Jorgen Ingerslev, David Habart, Zdena Vorlova, Lars Holmberg, Stefan Lethagen, John Pasi, Frank Hill, Mohammad Hashemi Soteh, Luciano Baronciani, Christer Hallden, Andrea Guilliatt, Will Lester and Ian Peake
This article has an Erratum 111(6):3299

Data supplements

Article Figures & Data

Figures

  • Figure 1

    Definition of 3 groups of index cases.

  • Figure 2

    Missense mutations in index cases with normal and abnormal multimers. Pre-pro VWF, showing exons and protein domains encoded. The upper panel shows singly occurring mutations resulting in an abnormal multimer profile. The lower panel shows singly occurring mutations resulting in a normal multimer profile. Three substitutions in bold displayed both normal and abnormal multimers in different index cases.

  • Figure 3

    Distribution of the VWF:RCo/VWF:Ag ratio in the 3 groups of index cases and healthy controls. The box plots indicate the median, interquartile range (box), extreme values (T bars), and outliers (○).

Tables

  • Table 1

    Phenotypic data for the cohort

    FVIII:CVWF:RCoVWF:AgVWF:CBVWF:RCo/VWF:AgBleeding score
    IC
        Arithmetic median, IU/dL (25th to 75th percentiles)58 (31-80)35 (13-53)38 (21-51)39 (20-60)0.92 (0.64-1.12)9.0 (4.5-13.0)
        No. of individuals150149150149149150
    AFM
        Arithmetic median, IU/dL (25th to 75th percentiles)65 (34-89)36 (13-55)37 (22-56)52 (24-80)0.93 (0.61-1.14)5.0 (2.0-8.0)
        No. of individuals27327027187270274
    UFM
        Arithmetic median, IU/dL (25th to 75th percentiles)103 (78-135)88 (65-113)93 (71-119)100 (78-121)0.95 (0.80-1.16)0.0 (−1.0-1.0)
        No. of individuals300295295111295303
    HC
        Arithmetic median, IU/dL (25th to 75th percentiles)108 (88-133)94 (75-117)97 (76-121)130 (103-150)1.00 (0.85-1.17)−1.0 (−1.0-0.0)
        2.5th to 97.5th percentiles57-19847-19448-16766-2260.59-1.62−3.0-3.0
        No. of individuals116011561156991156195
    • P values using the Mann-Whitney test are as follows:

    • FVIII:C IC versus AFM, P = nonsignificant (NS); versus UFM and HC, P < .001. UFM versus HC, P = .027.

    • VWF:RCo IC versus AFM, P = NS; versus UFM and HC, P < .001. UFM versus HC, P = .001.

    • VWF:Ag IC versus AFM, P = NS; versus UFM and HC, P < .001. UFM versus HC, P = NS.

    • VWF:CB IC versus AFM, P = .009; versus UFM and HC, P < .001. UFM versus HC, P < .001.

    • VWF:RCo/VWF:Ag IC versus AFM, P = NS; versus UFM, P = .015; versus HC, P < .001. UFM versus HC, P = .01.

    • Bleeding score (BS) IC versus AFM, UFM, and HC, P < .001. UFM versus HC, P < .001.

    • IC indicates index case; AFM, affected family member; UFM, unaffected family member; HC, healthy control.

  • Table 2

    Number of mutations and median phenotype in 150 index cases with type 1 VWD

    Multimer patternNo. of ICs per groupNo. of mutations per ICNo. of mutations per groupFVIII:C, IU/dLVWF:RCo, IU/dLVWF:Ag, IU/dLVWF:CB, IU/dLVWF:RCo/VWF:Ag,% blood group OBleeding score
    Group 1*
        AbM570, 1, or > 165341019190.536010.0
        AbM541 or > 165331019170.536110.0
        AbM43143331020190.506110.0
        AbM11> 122341113150.856412.0
        AbM300392836200.78336.0
    Groups 2+3
        NM930, 1, or > 159704547540.96678.0
    Group 2
        NM511 or > 159664245480.93608.0
        NM44144674345490.96617.5
        NM7> 115303847380.817110.0
    Group 3
        NM4200775149571.04768.0
    All
        AbM or NM1500, 1, or > 1124583538390.92659.0
    • P values using the Mann-Whitney test are as follows:

    • VWF:RCo group 1 versus 2 and group 1 versus 3, P < .001; group 2 versus 3, P = .033.

    • VWF:Ag group 1 versus 2 and group 1 versus 3, P < .001; group 2 versus 3, P = .127.

    • BS group 1 versus 2, P = .252; group 1 versus 3, P = .086; group 2 versus 3, P = .586.

    • * The groups represent categories of ICs: 1, abnormal multimers (AbM); 2, normal multimers (NM) with a mutation; 3, normal multimers (NM) without a mutation.

    • Phenotypic data are indicated as the median.

  • Table 3

    VWF mutations and phenotype in 43 group 1 index cases with abnormal multimers and a single mutation

    IC*Type of mutationExon/intronNucleotide changeAmino acid changeNo. of ICs with this mutationFVIII:C, IU/dLVWF:RCo, IU/dLVWF:Ag, IU/dLVWF:CB, IU/dLVWF:RCo/VWF:AgCosegregation (no. of families)
    P6F1II1§Missense202561G>A40R854Q1252332150.721
    P7F9I1SpliceInt202686−2A>GExon 21 skip1853644270.821
    P7F13II1SpliceInt212820+1G>CExon 21 skip168721150.331
    P5F8I3SpliceInt212820+1G>AExon 21 skip11153832331.191
    RangeMissense263388T>CC1130R313-157-1312-226-80.58-0.591 (1), 2 (1), 3 (1)
    P9F5II2Missense263388T>GC1130G181010261.001
    RangeMissense263389C>T30C1130F210-223-482-60.38-0.501 (1), 3 (1)
    P9F1I2Missense263430T>GW1144G1241231120.391
    RangeMissense273614G>A26R1205H57-19#3-105-104-60.40-1.431 (2), 2 (2), 3 (1)
    P3F1II1Deletion283831-3833delCCTD1277−E78delinsL122318200.171
    P6F3II1Missense283853T>CS1285P12731680.191
    P6F13II1Missense283920T>CL1307P13371660.441
    RangeMissense283943C>T39R1315C420-623-107-256-250.40-0.451 (2), 2 (2)
    P5F4II1Missense284024C>TR1342C143320280.151
    RangeMissense284120C>T20R1374C330-343-710-4510-190.07-0.701 (3)
    RangeMissense284121G>A20R1374H248-7910-1629-7422-230.22-0.342 (1), 3 (1)
    RangeMissense284244G>AG1415D213-183-141410-150.21-1.001 (1), 2 (1)
    P12F10II1Missense284247T>AI1416N143319200.161
    P2F22I2Missense325465T>GV1822G1352619451.373
    P5F9II2Missense386620T>C8L2207P1711926350.732
    P12F12II2Missense386769T>AC2257S1704229301.452
    P5F2II2Missense406911G>AC2304Y1421920370.953
    P2F16II2Missense427239C>T8.42C2362F1883435390.971
    P5F10II1Missense437321G>TG2441C1612022260.911
    RangeMissense437390C>TR2464C232-5225-3025-3337-500.91-1.001 (1), 3 (1)
    P7F22I2Missense437430G>AC2477Y1683338430.872
    P10F2I1Missense437430G>CC2477S1584028311.431
    P3F11II1Missense457559A>CQ2520P1482719191.422
    • * ICs are indicated by their study ID; when a mutation is present in more than 1 IC, the phenotypic data are indicated as “range.”

    • Novel mutations not previously reported on the ISTH VWF database.

    • Cosegregation of VWD with the VWF gene12; 1 indicates complete cosegregation; 2, incomplete cosegregation; 3, not informative.

    • § Reduced VWF:FVIIIB.

    • Excluded as an SNP by absence from 100 healthy controls.

    • Reduced VWF:FVIIIB in only 1 of the 3 ICs.

    • # One high outlier was excluded from the range of values shown but was included in all analyses.

  • Table 4

    VWF mutations and phenotype in 11 group 1 index cases with abnormal multimers and 2 mutations

    Type of mutation by IC*ExonNucleotide changeAmino acid changeNo. of ICs with this mutationFVIII:C, IU/dLVWF:RCo, IU/dLVWF:Ag, IU/dLVWF:CB, IU/dLVWF:RCo/VWF:AgCosegregation (no. of families)
    P1F4II1§ 1342519151.321
        Missense284751A>G21Y1584C
        Missense437390C>TR2464C
    P2F1II1§ 1739170.333
        Deletion284449delGL1481fs
        Missense284751A>G21Y1584C
    Range 33-143-66-145-180.43-0.751 (2), 3 (1)
        Missense172220G>A43M740I
        Missense273614G>A43R1205H
    P2F6II1§ 1551113ND0.851
        Missense263389G>T30C1130F
        Missense497988G>CR2663P
    P3F7II1§ 1123361.002
        Nonsense315335C>TR1779X
        Missense437405T>CS2469P
    P3F13I1 1781342240.311
        Missense212771G>A44R924Q
        Missense283944G>TR1315L
    P4F4I1§ 134310140.301
        Missense284120C>T20R1374C
        Missense376433C>TP2145S
    P5F3II2# 1651127420.411
        Missense283797C>T22P1266L
        Missense283944G>AR1315H
    P10F10II1 125131470.933
        Missense263437A>GY1146C
        Missense284133C>TS1378F
    • ND indicates not done.

    • * ICs are indicated by their study ID; when a mutation is present in more than 1 IC, the phenotypic data are indicated as “range.”

    • Novel mutations.

    • Cosegregation of VWD with the VWF gene12; 1 indicates complete cosegregation; 2, incomplete cosegregation; 3, not informative.

    • § Compound heterozygous inheritance of the 2 mutations.

    • Allelic inheritance of the 2 mutations.

    • Reduced VWF:FVIIIB.

    • # P1266L is the result of gene conversion with the VWF pseudogene VWFP. The IC also has 3789G>A; S1269.

  • Table 5

    VWF mutations and phenotype in 44 group 2 index cases with normal multimers and a single mutation

    IC*Type of mutationExon/intronNucleotide changeAmino acid changeNo. of ICs with this mutationFVIII:C, IU/dLVWF:Rco, IU/dLVWF:Ag, IU/dLVWF:CB, IU/dLVWF:RCo/VWF:AgCosegregation (no. of families)
    RangePromoterPromoter−2520C>T4745765610.881 (1), 2 (1), 3 (2)
    P12F2II1PromoterPromoter−1896C>T1754843691.123
    P6F7II3Missense255G>AG19R1802030200.672
    P9F17II2Missense5478G>TG160W1505253380.982
    P9F12II2Missense5497A>TN166I1552938220.761
    P2F15II1SpliceInt131534-3C>A811325355620.963
    P7F20II1Missense151922C>TA641V1566097770.622
    P9F16IV3Missense182313G>TM771I1205938491.552
    P7F2II1Deletion182435delC45P812fs1562928311.043
    P10F8II1Missense192446C>T40R816W1145249571.063
    P12F6II2SpliceInt202686-1G>CExon 21 skip11594251600.821
    P5F1II3§Missense202561G>A40R854Q1283237430.861
    P6F11II1Missense212771G>A44R924Q1523440490.853
    P3F10II1Deletion233072delCS1024fs1763831351.231
    P7F1I2Missense253281T>CI1094T11487471761.043
    P2F4I2Missense273614G>A26R1205H1113341.001
    P12F4II12Insertion283839-3845ins7F1280fs1663529591.211
    P12F7II2Missense284082T>CL1361S1861490350.161
    P10F3II1Missense284135C>T46R1379C11076059621.023
    P10F1II2Missense284238C>TP1413L1583944370.891
    P2F12II1Nonsense284423C>TQ1475X1363827481.411
    P7F4II1Missense284747C>T8R1583W1565452571.043
    RangeMissense284751A>G21Y1584C1021-18236-9321-8020-1150.75-1.241 (5), 2 (2), 3 (3)
    P7F11II1SpliceInt295170+10C>T1674539441.152
    P12F13II1Missense315321T>CL1774S11079764451.522
    P9F10II1Missense315380A>GK1794E1702634300.761
    P10F6II1Missense406911G>AC2304Y11506168710.901
    P3F91II1Missense406938G>AR2313H1705261600.852
    P5F6II3Missense457551G>AG2518S11145455650.981
    P8F2II2Nonsense457630C>T47Q2544X1754026431.543
    P6F16II1Missense498078G>AC2693Y1696446421.391
    P9F11II1Missense518164C>GP2722A152031310.651
    • — indicates not applicable.

    • * ICs are indicated by their study ID; when a mutation is present in more than 1 IC, the phenotypic data are indicated as “range.‘

    • Novel mutations.

    • Cosegregation of VWD with the VWF gene12; 1 indicates complete cosegregation; 2, incomplete cosegregation; 3, not informative.

    • § Reduced VWF:FVIIIB.

    • Excluded as an SNP by absence from 100 healthy controls.

    • Absent VWF:FVIIIB.

  • Table 6

    VWF mutations and phenotype in 7 group 2 index cases with normal multimers and more than 1 mutation

    Type of mutation by IC*Exon/intronNucleotide changeAmino acid changeFVIII:C, IU/dLVWF:Rco, IU/dLVWF:Ag, IU/dLVWF:CB, IU/dLVWF:RCo/VWF:AgCosegregation
    P7F14I1§ 936058951.032
        PromoterPromoter−3266G>C
        PromoterPromoter−2730C>T
        PromoterPromoter−2326T>G
    P2F3II1 94459380.753
        SpliceInt91109+2T>C
        Missense202561G>A40R854Q
    P5F11II1# 403847590.812
        Missense202561G>A40R854Q
        Missense284751A>G21Y1584C
    P7F3II1 153825381.523
        Missense202561G>A40R854Q
        Missense212771G>A44R924Q
    P10F4I2§ 30327220.113
        Missense202642T>GL881R
        Missense284263C>G8N1421K
    P6F5II1 1871160.641
        Missense212771G>A44R924Q
        Missense273614G>A26R1205H
    P7F16I1§ 1194947811.043
        Missense366187C>T8**P2063S
        Missense396859C>TR2287W
    • — indicates not applicable.

    • * ICs are indicated by their study ID.

    • Novel mutations.

    • Cosegregation of VWD with the VWF gene12; 1 indicates complete cosegregation; 2, incomplete cosegregation; 3, not informative.

    • § Allelic inheritance of 2 mutations.

    • Absent VWF:FVIIIB.

    • Compound heterozygous inheritance of 2 mutations.

    • # Reduced VWF:FVIIIB.

    • ** Frequency checked in matched local population; allele frequency, 0.025.

  • Table 7

    Association between the presence of mutations and VWF level in index cases

    VWF level in ICMutationNo mutationOR (95% CI)
    VWF:Ag, IU/dL
        More than 4527271*
        31 to 4524112.2 (0.90-5.3)
        16 to 303065.0 (1.8-14.0)
        0 to 1523123.0 (2.9-182.6)
    VWF:RCo, IU/dL
        More than 4523251*
        31 to 4524122.2 (0.89-5.3)
        16 to 301763.1 (1.04-9.2)
        0 to 1540221.7 (4.7-100.3)
    • OR indicates odds ratio; CI, confidence interval.

    • * Reference category.