AnInheritedBleedingDisorderLinkedtoaDefectiveInteractionbetweenADPandItsReceptoronPlatelets
PMID: 7706468
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This mentions a Glanzmann thrombasthenia patient; however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence
GT12
Case12: GT-12, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.2326_2331dupGAGGCC and Father: deceased
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe and bleeding time is pathogenic (See Table 1) Abstract mentions patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, GI bleeding and menorrhagia; however, not specified per proband.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry was performed and expression is stated as pathogenic in Table 1
PlateletAggregation: Platelet aggregation was performed and is stated as pathogenic in Table 1; however, no specific agonists mentioned
CasePreviousTesting: All exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were amplified by PCR using intronic primers as pre-viously described (12). The purified DNA fragments were then di-rectly sequenced.
Gene: ITGA2B
Variant: NM_000419.3:c.957T>A and NM_000419.3:c.2326_2331dupGAGGCC
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804780 and CA915940324
gnomAD: N/A
GT5
Case5: GT-5, Caucasian, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe and bleeding time is pathogenic (See Table 1) Abstract mentions patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, GI bleeding and menorrhagia; however, not specified per proband.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry was performed and expression is stated as pathogenic in Table 1
PlateletAggregation: Platelet aggregation was performed and is stated as pathogenic in Table 1; however, no specific agonists mentioned
CasePreviousTesting: All exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were amplified by PCR using intronic primers as pre-viously described (12). The purified DNA fragments were then di-rectly sequenced.
Gene: ITGA2B
Variant: NM_000419.3:c.408G>C and NM_000419.3:c.1787T>C
LegacyVariant: N/A
ClinVar: 2900
CAiD: CA500624244 and CA115846
gnomAD: MAF in the European (non-Finnish) population 0.00006484 http://gnomad.broadinstitute.org/variant/17-42463192-C-G and MAF in European (non-Finnish) population is 0.0001325 http://gnomad.broadinstitute.org/variant/17-42457148-A-G
Supplementary Table S1 & S2 Proband and Variant Information:
Case22: GT25, Male, 81, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002239
Gastrointestinal bleeding
CaseHPOFreeText: Life-long bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 and CA399801310
gnomAD: MAF in the European (non-Finnish) population 0.000008791 http://gnomad.broadinstitute.org/variant/17-42457994-G-C and MAF in Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
Red blood cell transfusion in patients with type 1 Glanzmann’sthrombasthenia
PMID: 16194208
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a proband with GT; however, there is no mention of variants in ITGA2B and/or ITGB3, therefore we have insufficient evidence
GT 24
Case6: GT24, Male, India, age of onset is 10 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.2898_2902dup
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940725
gnomAD: N/A
5
Case5: Female, 3 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225
(Epistaxis, gingival bleeding)
CaseHPOFreeText: Severe epistaxis and mild gum bleeding
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.859G>C (p.Gly287Arg)
LegacyVariant: (p.Gly256Arg)
ClinVar: N/A
CAiD: CA399805008
gnomAD: N/A
4
Case4: Female, 18 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000132
(Gingival bleeding, menorrhagia)
CaseHPOFreeText: Menorrhagia only during puberty
CaseNotHPOs: N/A
CaseNotHPOFreeText:N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.2264G>C (p.Arg755Pro)
LegacyVariant: (p.Arg724Pro)
ClinVar: N/A
CAiD: CA8602772
gnomAD: MAF in the European (non-Finnish) population is 0.00001060 https://gnomad.broadinstitute.org/variant/17-42454380-C-G
3
Case3: Male, 40 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0002239, HP:0002248
(Epistaxis, GI bleeding, hematemesis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.310+1G>A (IVS2(+1)G>A)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603502
gnomAD: MAF in the European (non-Finnish) population is 0.00001771 https://gnomad.broadinstitute.org/variant/17-42463377-C-T
2
Case2: Male, 3 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0030137 (Prolonged bleeding following circumcision)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.1652G>A (p.Arg551Gln)
LegacyVariant: (p.Arg520Gln)
ClinVar: N/A
CAiD: CA8602986
gnomAD: MAF in the South Asian population is 0.00006536 https://gnomad.broadinstitute.org/variant/17-42457470-C-T
10
Case10: Female, 7 years old, Indian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000790 (Epistaxis, hematuria)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa
PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)
CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed
Gene: ITGA2B
Variant: NM_000419.3:c.2415del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940581
gnomAD: N/A
Supplementary Table S1:
Case35: GT41a, Canadian/Chinese, gender and age not specified here
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.91del (p.Ala31ProfsTer2) and NM_000419.3:c.2915dup (p.Leu973AlafsTer63)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913203486 and CA8602531
gnomAD: MAF in the East Asian population is 0.0001088 https://gnomad.broadinstitute.org/variant/17-42452054-C-CG for the variant (p.Leu973Alafs*63)
Supplementary Table S1:
Case31: GT36a, Spain, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.131G>T (p.Gly44Val) and NM_000419.3:c.1440-13_1440-1del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806881 and CA913184940
gnomAD: N/A
Supplementary Table S1:
Case17: GT20, French, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: M_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290946484
gnomAD: N/A
Supplementary Table S1:
Case39: GT45, French, age and gender not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.551_626del (p.Arg184_Gln208del) and the other variant is noted as "LR deletion" and that is all the information we are given so I will note it as an Unknown Variant
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940373
gnomAD: N/A
Linkage disequilibrium amongstITGA2BandITGB3genevariants in patients with Glanzmann thrombasthenia confirmsthat most disease-causing mutations are recent
PMID: 27469266
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
See Page Notes for Supplementary Data
Alloimmunization in Congenital Deficiencies of Platelet Surface Glycoproteins: Focus on Glanzmann's Thrombasthenia and Bernard–Soulier's Syndrome
PMID: 29879742
Gene:ITGA2B
HGNC: 6138
InsufficientEvidence Variant IVS15(+1)G > A mutation in ITGA2B is mentioned in this article; however, no proband to tie variant to therefore we have insufficient evidence
GT-56
Case45: (GT-56) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.985G>T (p.Val329Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399804719
gnomAD: N/A
GT-46b
Case36: (GT-46) Female, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT45-GT48 are related
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1879-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290949031
gnomAD: N/A
Rapid diagnosis of the French gypsy mutation in Glanzmann thrombasthenia using high- resolution melting analysis
PMID: 20886184
Gene: ITGA2B
HGNC: 6138
InsufficientEvidence: Variant mentioned here; however, specific proband information is not provided here, probands are clumped together in cohort
Three novel mutations in the glycoprotein IIb gene in a patient with type II Glanzmann thrombasthenia
PMID: 17488698
Gene: ITGA2B
HGNC: 6138
Triplejeopardy:AcaseofGlanzmann'sthrombastheniawithanti-GPIIb-IIIaantibodiesandHPAincompatibilityresultinginstillbirth
PMID: 31404847
Gene: ITGA2B
HGNC: 6138
Perioperative Management of a Heterozygous Carrier of Glanzmann’s Thrombasthenia Submitted to Coronary Artery Bypass Grafting With Cardiopulmonary Bypass
PMID: 16861409
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This mentions a Glanzmann thrombasthenia patient; however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence
Catheter Intervention in a Patient with Intracranial Aneurysms and Glanzmann Thrombasthenia Caused by a Novel Homozygous Likely Pathogenic Variant in the ITGA2B Gene
PMID: 39057107
Gene: ITGA2B
GNC: 6138
13
Case2: Female, 41 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: "This mutation was confirmed in the proband and parents."
CasePresentingHPOs: HP:0000225 (Gingival bleeding)
CaseHPOFreeText: Site of bleeding: Skin
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: See Table 1 (information provided)
PlateletAggregation: See Table 1 (information provided)
CasePreviousTesting: Screened mutations in ITGA2B and ITGB3 by multiplex polymerase chain reaction (PCR) amplification (MPCR) and conformation-sensitive gel electrophoresis
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
23
Case23: Female, Arab, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000132)
(Epistaxis, menorrhagia)
CaseHPOFreeText: Haematuria
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.409-2_419del
LegacyVariant: N/A
ClinVar: 2889
CAiD: CA10575471
gnomAD: N/A
A novel homozygous splice junction mutation in GPIIb associated with alternative splicing, nonsense‐mediated decay of GPIIb‐mRNA, and type II Glanzmann's thrombasthenia C. González‐Manchón Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author E. G. Arias‐Salgado Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author N. Butta Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author G. Martín Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author R. B. Rodríguez Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author I. Elalamy Service d'Hématologie Biologique, Hôpital d'Enfants A Trousseau, Paris, FranceSearch for more papers by this author R. Parrilla Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; andSearch for more papers by this author R. Favier Service d'Hématologie Biologique, Hôpital d'Enfants A Trousseau, Paris, FranceSearch for more papers by this author
PMID: 12871379
Gene: ITGA2B
HGNC: 6138
A 62‐year‐old Egyptian male
Case#: Male, 62, Egyptian
DiseaseAssertion: GT with concurrent platelet CD36 deficiency (~1 in 100 million) and anti‐CD36 antibodies
CasePresentingHPOs: HP:0000421,Epistaxis. HP:0000978, Bruising susceptibility. HP:0000225, Gingival bleeding. HP:0001903, Anemia. HP:0001934, Persistent bleeding after trauma. HP:0001058, Poor wound healing. HP:0002573, Hematochezia. HP:0005261, Joint hemorrhage.
PlateletAggregation: See Table 1. Normal platelet count. Normal platelet size, modestly elevated mean platelet volume. Normal response to ristocetin.
ProteinExpression: Flow cytometry. GPIb/IX Expression 108% (range: 65-124%); GPIIb/IIIa expression 0% (range:65-124%).
Gene: ITGA2B
Variant: c.2148dup, p.Leu717Alafs3X
HGVS: NM_000419.5:c.2148dup
ClinVar: 627273
CAID: CA915940304
gnomAD: Absent
Variant: c.1234G>A, p.Gly412Arg
HGVS: NM_000419.5:c.1234G>A
ClinVar: 381748
CAID: CA8603182
gnomAD: 0.00003236, https://gnomad.broadinstitute.org/variant/chr17-44381038-C-T?dataset=gnomad_r4
In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
PMID: 28808266
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions 7 Glanzmann thrombasthenia variants that were identified in a long independent molecular dynamics simulation. There are no probands with these variants mentioned.
M1
Case1: Patient M1, Female, French Gypsy, age is not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Figure 2 for pedigree
ParentalGenotype: Unaffected parents see pedigree Fig 2
CasePresentingHPOs: N/A
CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)
PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
Case 1
Case1: Female, 9 years old, Japanese
DiseaseAssertion: Macrothrombocytopenia
FamilyInfo: Information given in Table 1 and Fig 2
ParentalGenotype: Mother: ITGA2B (p.Arg422Ter heterozygous) and Father: ITGA2B (p.Gly991Cys heterozygous) See Table 1 for this information
Sequencing of parental DNA indicated parental mutations. CasePresentingHPOs: HP:0000979, HP:0000421, HP:0000978
(Purpura, epistaxis, bruising)
CaseHPOFreeText: Hemorrhage after dental
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometric analysis showed that surface αIIbβ3 expression in platelets (was markedly impaired 3-11%)
PlateletAggregation: N/A
CasePreviousTesting: Sequence analysis of entire coding regions of exons and exon-intron boundaries of ITGA2B and ITGB3 gene of the patient revealed two novel mutations in ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.3064G>T (p.Gly1022Cys) and NM_000419.3:c.1357C>T (p.Arg453Ter)
LegacyVariant: (p.Gly991Cys legacy nomenclature for p.Gly1022Cys) and (p.Arg422Ter legacy nomenclature for p.Arg453Ter)
ClinVar: 631773
CAiD: CA399787943 and CA399803529
gnomAD: N/A
Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype
PMID: 24498605
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
Case1: Male, 61 years old, Iraqi-Jewish origin
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: His sister is the other proband in this article
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000225, HP:0000225, HP:0031364, HP:0002249
(Gingival bleeding, epistaxis, ecchymosis, melena)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Surface expression GPIIb/IIIa was 9% of normal
PlateletAggregation: Platelet aggregation in response to thrombin, collagen, ADP and epinephrine was absent, whereas ristocetin induced aggregation was normal
CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the GPIIb gene were amplified by PCR
Gene: ITGA2B
Variant: NM_000419.3:c.1947-2A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399801096
gnomAD: N/A
Inherited Bleeding Disorders in the Obstetric Patient
PMID: 30097224
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mentions Glanzmann thrombasthenia probands or vairants
Glanzmann thrombasthenia in Pakistan: molecular analysis and identification of novel mutations
PMID: 26096001
Gene: ITGB3 and ITGA2B
HGNC: 6156 and 6138, respectively as shown above
Supplementary Tables 1 and 2 combined information:
Case40: GT40, Male, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.962G>T (p.Gly321Val)
LegacyVariant: N/A
ClinVar: 2892 (p.Arg584Ter)
CAiD: CA115834 (p.Arg584Ter) and CA399804765 (p.Gly321Val)
gnomAD: MAF for p.Arg584Ter in East Asian population 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case3: GT3, Female, 12 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3: c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case6: GT6, Male, 7 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small amount of response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.812C>G (p.Ala271Gly) and NM_000419.3:c.2172G>A (p.Met724Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805123 (p.Ala271Gly) and CA399798895 (p.Met724Gln)
gnomAD: N/A
Understanding the genetic basis of Glanzmann thrombasthenia: implications for treatment
PMID: 23146053
Genes: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions many variants in ITGA2B and ITGB3; however, no probands are mentioned in this review.
DISORDERS OF PLATELET FUNCTION
PMID: 1321709
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article is a review on Glanzmann thrombasthenia, it does not mention specific patients or variants in ITGA2B and/or ITGB3; however, it does mention probands in other papers
PreviouslyPublished: PMID: 1702098, 1967954
20.
Case20: Female, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Moderate bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.889G>A (p.Gly296Arg) **authors say (Gly297Arg) but ensembl shows Gly296Arg
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603304
gnomAD: MAF in the South Asian population is 0.0003267https://gnomad.broadinstitute.org/variant/17-42461681-C-T
13.
Case13: Female, African, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.1357C>T (p.Arg453Ter)
LegacyVariant: N/A
ClinVar: 631773
CAiD: CA399803529
gnomAD: N/A
M16
Case24: (M16) Male, 52 years old, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Failed to express alphaIIbbeta3 on the surface of their platelets
Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)
CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD N/A
M1
Case9: (M1) Male, 9 years old, French Gypsy
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
ProteinExpression: Failed to express alphaIIbbeta3 on the surface of their platelets
Platelet Aggregation: Absent platelet aggregation to all agonists (no mention for which agonists or response to ristocetin)
CasePreviousTesting: All the information we are given is "mutation screening of the ITGA2B and ITGB3 genes" the method for sequencing etc. was not stated
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD N/A
Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study
PMID: 25539746
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
Table 3 Molecular Diagnosis of Patients with Glanzmann Thrombasthenia:
Case3: GT-3, age, gender, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type II
FamilyInfo: Segregation analysis confirmed in presence of heterozygous mutations in this proband.
ParentalGenotype: Although segregation analysis confirmed, we do not know which variant in particular came from mom or dad.
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients presented with a variable bleeding diathesis; most patients had epistaxis (54%), cutaneous bleeding (58%), and menorrhagia (100% of women) while other common symptoms (oral cavity, GI, following dental extraction of mild injuries, postpartum, or hematomas) were in general milder. There is no specific phenotypes attached to probands in this paper.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed that αIIbβ3 expression was between 5% and 20%.
PlateletAggregation: There was severely impaired aggregation in response to all physiological agonists, and ristocetin induced platelet agglutination was normal or reduced to some extent.
CasePreviousTesting: Total RNA from peripheral blood was used for cDNA synthesis for RT-PCR. Then, using specific oligonucleotides and conditions, they amplified and sequenced ITGA2B and ITGB3 by Sanger sequencing. Every mutation found in cDNA was confirmed in DNA samples.
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Arg705Cys)
LegacyVariant: (p.Cys674Arg)
ClinVar: N/A
CAiD: CA8602816
gnomAD: MAF in European non-Finnish population is 0.000008792
The biologic and clinical spectrum of Glanzmann’s Thrombasthenia:implications of integrinaIIbb3for its pathogenesis
PMID: 9246538
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article is a review and goes over many patients from the Glanzmann thrombasthenia database https://glanzmann.mcw.edu/
PreviouslyPublished: All these probands have been previously published in the GT database https://glanzmann.mcw.edu/ please search the database to get info. There are no "new' case reports in this article
A Single Amino Acid Substitution Flanking the Fourth Calcium Binding Domain of aIm Prevents Maturation of the aImp, Integrin Complex
PMID: 7508443
Gene: ITGA2B
HGNC: 6138
cases 1
Case1: Female, 25 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A per Table 1
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Prolonged ivy bleeding times, bleeding diathesis since early childhood
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Surface expression of αIIbβ3 was analyzed by flow cytometry which was < 5% of normal
PlateletAggregation: Aggregation in response to ADP, epinephrine and collagen was absent but normal in response to ristocetin
CasePreviousTesting: Nucleotide sequences of the αIIb and β3 coding regions were determined by direct sequencing of RT-PCR products from platelet RNA.
Gene: ITGA2B
Variant: NM_000419.3:c.959T>C (p.Phe320Ser)
LegacyVariant: (p.Phe289Ser)
ClinVar: N/A
CAiD: CA399804774
gnomAD: N/A
GTP1
Case1: GTP1, gender, age, or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Sequencing of both parental genomic DNA confirmed patient was homozygous for IVS4+1G>A mutation
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% αIIbβ3 expression, which was confirmed by western blot analysis
PlateletAggregation: N/A
CasePreviousTesting: Sequencing of patient genomic DNA was done on ITGA2B (no mention of ITGB3)
Gene: ITGA2B
Variant: NM_000419.3:c.574+1G>A (IVS4+1G>A)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805691
gnomAD: MAF in the European non-Finnish population 0.00001235 http://gnomad.broadinstitute.org/variant/17-42462918-C-T
17
Case17: Patient MO (patient found in the GT database as well) gender and age are not specified here
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000132 (Bruising, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
PreviouslyPublished: Reference numbers 29 and 30 in this article
LeM
Case10: Patient LeM (found in the GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000979, HP:0000967 (Purpura/petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <5% of normal expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1366_1371del
LegacyVariant: N/A
ClinVar: 2898
CAiD: CA8603160
gnomAD: MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42458268-TGTCTAC-T
PreviouslyPublished: Reference number 21 in this article
CG
Case20: Patient CG (Found in GT database) also gender and age are not specified for this patient
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: Gingival bleeding and menorrhagia HP:0000225, HP:0000132
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: About 5% of normal GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1787T>C and M_000419.3:c.3060+2T>C
LegacyVariant: N/A
ClinVar: 2900
CAiD: CA115846 and CA290944108
gnomAD: MAF in the European (non-Finnish) population is 0.0001325 https://gnomad.broadinstitute.org/variant/17-42457148-A-G and MAF in the European (non-Finnish) population is 0.00003876 https://gnomad.broadinstitute.org/variant/17-42451720-A-G
PreviouslyPublished: References 34 and 35 in this article
4LW
Case4: Patient LW (found in GT database)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0006298
(Bruising, Epistaxis, Prolonged bleeding after tooth extraction)
CaseHPOFreeText: Blood transfusions were needed
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 12% of normal GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.641T>C (p.Lue214Pro)
LegacyVariant: (p.Leu183Pro)
ClinVar: 2901
CAiD: CA115848
gnomAD: N/A
PreviouslyPublished: References 14 and 15
QUANTITATIVE ISOLATION OF RNA FROM HUMAN PLATELETS.
PMID: 1716379
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia probands with variants in ITGA2B and/or ITGB3; therefore, there is no evidence
Perioperative management of Glanzmann's syndrome: how we did it!
PMID: 20182353
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions an individual with GT; however, there is no mention of ITGA2B and/or ITGB3 variants in this individual
Patient 4
Case4: Patient 4, Female, 12 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected sister is Patient 3
ParentalGenotype: N/A (Not consanguineous Caucasians, showed no increased bleeding tendency)
CasePresentingHPOs: HP:0000967
(Petechiae)
CaseHPOFreeText: Hematomas, prolonged in vitro bleeding time
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis revealed that there was no surface expression of GPIIb/IIIa for Patient 4 and there was approx. 1520 of GPIIb/IIIa expression for Patient 4.
PlateletAggregation: All patients' platelets showed severely reduced platelet aggregation after stimulation with collagen and ADP in contrast to the normal range (See Table 1). Stimulation with epinephrine and arachidonic acid also demonstrated decreased platelet aggregation. In contrast, ristocetin-induced platelet aggregation was within a normal range.
CasePreviousTesting: Sequenced ITGA2B and ITGB3 genes from one patient of each family (Patient 2 and 3) and Patient 1 and 4 were screened for the identified mutation in the corresponding family.
Gene: ITGA2B
Variant: NM_000419.3:c.1787T>C (p.Ile596Thr)
LegacyVariant: N/A
ClinVar: 2900
CAiD: CA115846
gnomAD: MAF in the European (non-Finnish) population is 0.0001325 http://gnomad.broadinstitute.org/variant/17-42457148-A-G
Platelet aggregation induced by the C‐terminal peptide of thrombospondin‐1 requires the docking protein LAT but is largely independent of αIIb/β3 C. Trumel INSERM, Unité 563, Centre de Physiopathologie Toulouse Purpan, Department of Oncogenesis and Cell Signaling in Hematopoetic Cells, Hôpital Purpan, Toulouse;Search for more papers by this author M. Plantavid INSERM, Unité 563, Centre de Physiopathologie Toulouse Purpan, Department of Oncogenesis and Cell Signaling in Hematopoetic Cells, Hôpital Purpan, Toulouse;Search for more papers by this author S. Lévy‐Tolédano INSERM, Unité 348, Hôpital Lariboisière, Paris;Search for more papers by this author A. Ragab INSERM, Unité 563, Centre de Physiopathologie Toulouse Purpan, Department of Oncogenesis and Cell Signaling in Hematopoetic Cells, Hôpital Purpan, Toulouse;Search for more papers by this author J. P. Caen IVS, Hôpital Lariboisière, Paris; andSearch for more papers by this author E. Aguado Center d'Immunologie de Marseille‐Luminy, INSERM‐CNRS‐University Medical Case 906, Marseille, FranceSearch for more papers by this author B. Malissen Center d'Immunologie de Marseille‐Luminy, INSERM‐CNRS‐University Medical Case 906, Marseille, FranceSearch for more papers by this author B. Payrastre INSERM, Unité 563, Centre de Physiopathologie Toulouse Purpan, Department of Oncogenesis and Cell Signaling in Hematopoetic Cells, Hôpital Purpan, Toulouse;Search for more papers by this author
PMID: 12871507
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions probands with GT; however, there are no variants in ITGA2B and/or ITGB3, in these probands noted in the article
A female patient
Case1: Female, 20 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421,
(Easy bruising, epistaxis)
CaseHPOFreeText: Prolonged bleeding time (more than 20 minutes, absent clot retraction
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Decreased of surface expression of αIIb and β3 in patient's platelets
PlateletAggregation: Absent in vitro platelet aggregation in response to ADP, epinephrine, and collagen, but relatively normal ristocetin induced platelet aggregation
CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of ITGA2B and ITGB3 genes were produced by PCR using primers. Amplified fragments were subjected to analysis by direct DNA sequencing
Gene: ITGA2B
Variant: NM_000419.3:c.527C>A (p.Pro157His)
LegacyVariant: (p.Pro126His)
ClinVar: N/A
CAiD: CA8603447
gnomAD: MAF in the African population is 0.00006689 http://gnomad.broadinstitute.org/variant/17-42462966-G-T
Identification of compound heterozygous mutations in the ITGA2B gene in a Chinese patient with Glanzmann thrombasthenia.
PMID: 20819594
Gene: ITGA2B
HGNC: 6138
FO
Case7: Patient FO
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs:
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: NM_000419.3:c.2153dup and NM_000419.3:c.1234G>A (p.Gly412Arg)
LegacyVariant: (p.Gly381Arg)
ClinVar: 381748
CAiD: CA913189170 and CA8603182
gnomAD MAF in the Latino population is 0.0001453 https://gnomad.broadinstitute.org/variant/17-42458406-C-T
DC
Case5: Patient DC
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs:
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1G>A
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD N/A
StopMB
Case14: Patient MB
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: NM_000419.3:c.1211-78A>G
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940720
gnomAD: N/A
Inhibitory and activating human antiplatelet antibodies
PMID: 10097812
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention GT patients with variants in ITGA2B and/or ITGB3; therefore there is no evidence
patient 3
Case3: Patient 3, Female, 27 years old
DiseaseAssertion: Glanzmann thrombasthenia type I (Diagnosed at 10 years old)
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding phenotypes are not specified per patient in this article, rather, it states: "Petechia, epistaxis, and prolonged bleeding after trauma were the most common symptoms among studied patients"
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: This patient has type 1 Glanzmann thrombasthenia; therefore, according to this article, this proband had between 0-5% of normal levels of surface GPIIb/IIIa expression.
PlateletAggregation: Prolonged bleeding time, abnormal clot retraction, impaired platelet aggregation induced by most physiological agonists (ADP, epinephrine, and collagen) except ristocetin, mucosal bleeding, easy bruising, epistaxis, as well as normal prothrombin/activated partial thromboplastin time, and normal platelet count. (This is among inclusion criteria for this study)
CasePreviousTesting: To identify the underlying molecular mechanism of GPIIb/IIIa complex abnormalities among probands in this study, all the 30 exons of ITGA2B and the 15 exons of ITGB3 were analyzed using PCR–CSGE and DNA sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.113del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940264
gnomAD: N/A
The patient
Case1: Male, 7 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See pedigree Fig 5
ParentalGenotype: Parents heterozygous for the mutation proband has
CasePresentingHPOs:
(Petechia, bruising
CaseHPOFreeText: Mucocutaneous hemorrhages
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: There was a lack of platelet surface expression of the GPIIb-IIIa complex as shown by Western blotting
PlateletAggregation: Platelets fail to aggregate spontaneously or in response to agonists, although they agglutinate in response to ristocetin
CasePreviousTesting: Screening of mutations in both ITGA2B and ITGB3 was carried out by single stranded conformational polymorphism (SSCP) analysis
Gene: ITGA2B
Variant: NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: (p.Arg597Ter)
ClinVar: N/A
CAiD: CA399801310
gnomAD: MAF in the Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
Phosphatidylserine exposure, microparticle formation and mitochondrial depolarisation in Glanzmann thrombasthenia platelets
PMID: 24477274
Gene: ITGA2B
HGNC: 6138
P4
Case4: P4, gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Article mentions all patients have a severe bleeding phenotype
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: αIIbβ3 expression levels were (0.6% in patient 4)
PlateletAggregation: N/A
CasePreviousTesting: Acknowledgements section mentions acknowledging the Genoscope team for sequencing both ITGA2B and ITGB3 genes of the GT patients in this article
Gene: ITGA2B
Variant: NM_000419.3:c.857T>A (p.Val268Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805011
gnomAD: N/A
Osteopetrosis and Glanzmanns thrombasthenia in a child
PMID: 12707732
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a Glanzmann thrombasthenia patient with osteoporosis; however, the article does not mention specific variants in ITGA2B and/or ITGB3 in the proband. Rather, the discussion mentions other variants in ITGA2B and/or ITGB3 therefore we have insufficient evidence
The use of recombinant FVIIa in a patient with Glanzmann thrombasthenia with uncontrolled bleeding after tonsillectomy.
PMID: 19657319
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a patient with GT; however, no variants in ITGA2B and/or ITGB3 mentioned here
Case1: Female, 48 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000978, HP:0000132, HP:0006298, HP:0005261
(Epistaxis, gingival bleeding, easy bruising, menorrhagia, bleeding after tooth extraction, hemarthrosis
CaseHPOFreeText: Hemorrhage after surgery
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Platelet surface glycoprotein analysis by flow cytometry revealed a severe αIIbβ3 deficiency (Table 3 shows specific values)
PlateletAggregation: There was a failure of ADP, collagen and adrenalin to induce platelet aggregation, but ristocetin-induced platelet aggregation (RIPA) was normal
CasePreviousTesting: Integrin alphaIIb subunit gene (ITGA2B) sequencing showed that this proband was a compound heterozygote
Gene: ITGA2B
Variant: NM_000419.3:c.1214T>C (p.Ile405Thr) and NM_000419.3:c.1234G>A (p.Gly412Arg)
LegacyVariant: (p.Ile374Thr) (p.Gly381Arg)
ClinVar: 381748
CAiD: CA290950815 (p.Ile403Thr) and CA8603182 (p.Gly412Arg)
gnomAD: MAF in Latino population 0.0001453 http://gnomad.broadinstitute.org/variant/17-42458406-C-T
The Role of the Platelet Glycoprotein IIb/IIIa in Thrombosis andHaemostasis
PMID: 15134555
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia patients or variants in ITAG2B and/or ITGB3. This article gives more background on the molecular mechanisms of Glanzmann thrombasthenia
Alterations of the platelet proteome in type I Glanzmann thrombasthenia caused by different homozygous delG frameshift mutations in ITGA2B
PMID: 29385657
Gene: ITGA2B
HGNC: 6138
Analysis of platelet membrane glycoprotein polymorphisms in Glanzmann thrombasthenia showed the French gypsy mutation in the αIIb gene to be strongly linked to the HPA‐1b polymorphism in β3
PMID: 12871468
Gene: ITGA2B
HGNC: 6138
GT14
Case35: (GT14) Gender, age and ethnicity are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)
CaseNotHPOs: N/A
ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting
Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)
CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.
Gene:
Variant: NM_000419.3:c.188+8del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8603523
gnomAD MAF in the South Asian population is 0.0002613 https://gnomad.broadinstitute.org/variant/17-42466645-AC-A
A 56-year-old Japanese female
Case1: Female, 56 years old, Japanese
DiseaseAssertion: Glanzmann thrombasthenia (Diagnosed at 21 years of age)
FamilyInfo:
ParentalGenotype:
CasePresentingHPOs: HP:0004406, HP:0000225
(Recurrent epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry demonstrated significantly decreased expression of CD41 and CD61 to less than 20% of normal levels (See Figure 2)
PlateletAggregation: An in vitro assay revealed no platlet aggregation in response to agonists except ristocetin.
CasePreviousTesting: DNA sequencing analysis revealed compound heterozygous mutations confirming a diagnosis of Glanzmann thrombasthenia
Gene: ITGA2B
Variant: NM_000419.3:c.2602-3C>G and NM_000419.3:c.641T>C (p.Leu214Pro)
LegacyVariant: N/A
ClinVar: 2893 and 2901
CAiD: CA10575472 and CA115848
gnomAD: MAF in East Asian population 0.00006523 http://gnomad.broadinstitute.org/variant/17-42453087-G-C
Patient F4.II.1
Case#: Male, 48
Disease: Glazmann's Thrombasthenia Like Syndrome
CasePresentingHPOs: HP:0001873, HP:0000421, HP:0031364, HP:0000225
Thrombocytopenia, Epistaxis, Ecchymosis, Gingival bleeding
CaseNotHPOs: NA
FamilyInfo: Pedigree figure 1. Family history of thrombocytopenia.
PlateletAgreggation: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination
GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.
ClinVar: 50232
CAID: CA10575572
Variant: NM_000419.5:c.3077G>A
GnomAD: European non-Finnish 0.000008801 (1/113618)
ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 49%, CD61 (GPIIIa) 44%, and CD42b (GPIb) 105%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).
12
Case12: (Proband CabGT-12), Female, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed 19% GPIIb and 40% GPIIIa surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.2113T>C (p.Cys705Arg) and NM_000419.3:c.3060+2T>C (p.Val982_Lys1020del)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602816 and CA290944108
gnomAD MAF in the European (non-Finnish) population is 0.000008792 https://gnomad.broadinstitute.org/variant/17-42455140-A-G and MAF in the European non Finnish population for (p.Val982_Lys1020del) is 0.00003876 https://gnomad.broadinstitute.org/variant/17-42451720-A-G
AVariantFormofThrombasthenia
PMID: 1908636
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a Glanzmann thrombasthenia patient; however, there is no mention of variants in ITGA2B and/or ITGB3; therefore, there is insufficient evidence
Case9: Patient MR, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.1214T>C (p.Ile374Thr)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950815
gnomAD: N/A