Case120682: 62 year old Caucasian female

DiseaseAssertion: LVNC

FamilyInfo: family history was negative for cardiomyopathy or CHF, one daughter was noted to have a persistent high resting pulse

CasePresentingHPOs:

CaseHPOFreeText: first degree AV-block on ECG and prominent trabeculations at the left ventricular (LV) apex, mild aortic regurgitation

CaseNotHPOs:

CaseNotHPOFreeText:pulmonary hypertension

CasePreviousTesting: 41 cardiomyopathy-associated genes

GenotypingMethod: next generation sequencing and variant analysis, WES or WGS

Variant: NM_000257.4:c.732+1G>A

ClinVar: 14127

CAID: CA016715

gnomAD: 0.00005437 East Asian

https://gnomad.broadinstitute.org/variant/14-23900793-C-T

CaseHCM003: 31 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0002875, HP:0031295, HP:0006698, HP:0001705 (Exertional dyspnea, Left atrial enlargement, Dilatation of the ventricular cavity, Right ventricular outlet obstruction)

HPOsFreeText: Maximal LV thickness 29 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)

ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: Not in gnomAD

CaseHCM014: 43 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy)

HPOsFreeText: Maximal LV thickness 27 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00004657, http://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseHCM133: 64 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 21 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3551A>T (p.Gln1184Leu)

ClinVar: 181226 https://www.ncbi.nlm.nih.gov/clinvar/variation/181226/

gnomAD: 0.0006115, http://gnomad.broadinstitute.org/variant/14-23889229-T-A

Multiple Gene Variants

(1) MYH6 Variant

Variant: NM_002471.3(MYH6):c.1252G>A (p.Val418Met)

ClinVar: 44449 https://www.ncbi.nlm.nih.gov/clinvar/variation/44449/

gnomAD: 0.001954, http://gnomad.broadinstitute.org/variant/14-23870076-C-T

CaseHCM083: 53 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0001667, HP:0001705 (Exertional dyspnea, Left ventricular hypertrophy, Right ventricular hypertrophy, Right ventricular outlet obstruction)

HPOsFreeText: Maximal LV thickness 18 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23887429-C-T

CaseHCM051: 39 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of hypertrophic cardiomyopathy, Has 2 siblings where the MYH7 and MYOZ2 mutations are solely present in the brother and sister respectively, Brother has LVH and palpitations while sister has no symptoms whatsoever

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 18 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.3424G>A (p.Glu1142Lys)

ClinVar: 181222 https://www.ncbi.nlm.nih.gov/clinvar/variation/181222/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) MYOZ2 Variant

Variant: NM_016599.4:c.326C>G (p.Pro109Arg)

CAID: CA104971226 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA104971226

gnomAD: Not in gnomAD

Case1: male fetus

DiseaseAssertion: LVNC

FamilyInfo: first two pregnancies had resulted in miscarriages due to cervical insufficiency. The third pregnancy (after cerclage) resulted in a healthy nondysmorphic female with mild Ebstein anomaly of the tricuspid valve. The father was reported to have a history of a cardiac murmur and possible “hole in the heart.” Fetal echocardiography revealed that our patient's second child (fourth pregnancy) also had mild Ebstein anomaly. Father also has Ebstein anomaly, with significant apical displacement of the tricuspid valve, moderate tricuspid valve insufficiency, and right heart enlargement

CasePresentingHPOs: HP:0010316, HP:0031195

"Ebstein anomaly of the tricuspid valve, Apical hypertrabeculation of the left ventricle"

CaseHPOFreeText: mild apical displacement of the tricuspid valve, presence of multiple trabeculations on parasternal short‐axis and apical 4‐chamber views, with deep intertrabecular recesses

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: echocardiogram, Peripheral blood samples use to test 46 genes initially (including MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

GenotypingMethod: Testing was performed by oligonucleotide‐based target capture, followed by next generation sequencing. Sanger sequencing was used to provide data in areas with insufficient coverage and confirm clinically significant and novel variants. Heterozygous.

VariantMYH7: NM_000257.4:c.3658_3660del

ClinVar: 42968

CAID: CA013921

gnomAD: not reported

**VariantTTN: c.25722_25724delAGA (p.Glu8576del)

Allele registry currently not working

CaseV-4: Female, 11 years old

DiseaseAssertion: CFTD and LVNC

FamilyInfo: Multigenerational Italian family. Phenotypic data were available for 10 individuals (3 males and 7 females) ranging in age from 4 to 50 years old. All individuals were of Caucasian ancestry. DNA was available for 6 individuals (IV-10, IV-13, IV-14, V-1, V-4, V-5). Authors identified a mild LVNC phenotype in the mother (IV-14), sister (V-5) and cousin (V-1) of the proband, with hypertabeculations of the mid inferolateral wall and of the ape and without neuromuscular disorders. During the growth, there was a reduction of clinical signs in patients V-1 and V-5. No data have been collected for individual IV-9, who died at the age of 35 of unknown causes. The father (IV-13) of the proband was asymptomatic.

Proband is the first child of a family with a history of consanguinity (mother’s parents are first-degree cousins) and diabetes in the maternal line (grandmother, one great-uncle, one uncle and a first-degree cousin) without neuromuscular diseases.

LVNC segregated as a dominant mode of inheritance with high phenotypic heterogeneity and reduced penetrance. CFTD phenotype showed a recessive mode of inheritance.

CasePresentingHPOs: HP:0001290, HP:0002033, HP:0001643, HP:0001655, HP:0001374, HP:0004325, HP:0001943, HP:0001508, HP:0002515, HP:0002650, HP:0001284

"Generalized hypotonia, poor suck, Patent ductus arteriosus, Patent foramen ovale, Congenital hip dislocation, Decreased body weight (below 3rd percentile), Hypoglycemia, Failure to thrive, waddling gait, Scoliosis, Areflexia

CaseHPOFreeText: persistent crying, Persistent arterial duct and patent foramen ovale were diagnosed at birth but resolved spontaneously, as shown by echocardiography at the age of 1 month, congenital dislocation of the left hip, at 17 months of age hospitalized due to body weight below the third percentile and hypoglycemia, difficulties in chewing and swallowing, inability to stand up from a sitting position, a slight degree of weakness of the facial and masticator muscles, mild weakness of the glutei and ileo-psoas and marked bilateral quadriceps, Tendon reflexes were absent. Joints contractures had never been observed, A blood test confirmed hypoglycemia and normal levels of serum creatine kinase and isoenzymes, quadriceps muscle biopsy displayed a predominance of type 1 fibers

CaseNotHPOs:

CaseNotHPOFreeText: internal nuclei, nemaline bodies, cores were observed

CasePreviousTesting: Authors extended the clinical and instrumental (EMG, ECG, Echocardiography, muscle biopsy) evaluation to the whole family, Echocardiography showed a slight left ventricular (LV) dilatation, a moderate reduction of the LV global function (ejection fraction 40%), and a non-compacted aspect of the overall infero-lateral wall. The karyotype and FISH were normal. The serum creatine kinase (CK) was within the normal range, Dystrophin, emerin, calpain and lamin A/C were examined and found to be normal, cardiological investigation confirmed a long QTc and showed signs of left ventricular hypertrophy and repolarization abnormalities in the ECG, performed a thorough survey of all previously identified CFTD and LVNC genes to definitively exclude their involvement in the disease phenotype. Only intronic polymorphic variants were detected in TPM3, ACTA1, TPM2, MYL2, MYL3, G4.5, DTNA, ZASP, ACTC1, MYBPC3 and TMP1. Both intronic and coding polymorphic variants were detected in SEPN1, RYR1, MYH7, LMNA/C, TNNT2 and TNNI3

GenotypingMethod: Whole-exome sequencing of the proband and her cousin

VariantMYH7B: NM_020884.5:c.2668C>T

ClinVar:

CAID: CA9827409

gnomAD: https://gnomad.broadinstitute.org/variant/20-33582046-C-T

Case7: GT-7, German and Jugoslav, gender or age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: Mother: c.1126-72C>T heterozygous and Father: c.1126-72C>T heterozygous

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: ITGB3

Variant: NM_000212.2:c.1030dup and an Unregistered Variant (c.1126_72C>T) (Does not show up in CAR)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA658820875 and N/A

gnomAD: N/A

Case1: GT-1, Turkish, gender or age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: Mother: c.2374delG heterozygous and Father: c.2374delG heterozygous

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.2374del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940267

gnomAD: N/A

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

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

Case6: GT-6, Croats, 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: ITGB3

Variant: NM_000212.2:c.166–2A>G

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered Variant

gnomAD: N/A

Case1: Patient 9, Female, 10 years old

DiseaseAssertion: Glanzmann thrombasthenia III (Diagnosed at 3 months of age)

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 III Glanzmann thrombasthenia; therefore, according to this article, this proband showed normal or near-nromal levels of the GPIIb/IIIa complex via flow cytometry.

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/acivated 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: ITGB3

Variant: NM_000212.2:c.719G>A (p.Arg240Gln)

LegacyVariant: N/A

ClinVar: 13553

CAiD: CA123224

gnomAD: N/A

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

Supplementary Table S1 & S2 Proband and Variant Information:

Case62: GT65, Female, 31 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0000790, HP:0002239, HP:0006298

(Epistaxis, gingival bleeding, menorrhagia, hematuria, GI bleeding, bleeding after dental procedure)

CaseHPOFreeText: Tonsil bleeding, muscle hematomas

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.574+1G>A and NM_000419.3:c.1946+3G>T

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805691 and CA626121071

gnomAD: MAF in the European (non-Finnish) population is 0.00001235 https://gnomad.broadinstitute.org/variant/17-42462918-C-T and MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42456008-C-A

Supplementary Table S1 & S2 Proband and Variant Information:

Case13: GT14, Female, 10, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000979 and HP:0006298

(Purpura, prolonged bleeding after dental extraction)

CaseHPOFreeText: Moderate cutaneous bleeding from birth

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed <5% variant 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.423G>T (p.Trp141Cys) and NM_000419.3:c.2902del (p.Tyr968Metfs*163)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399806022 and CA915940332

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case51: GT51, Male, 29 years old, French/African

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421 (Epistaxis)

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGB3

Variant: NM_000212.2:c.861del (p.Arg287Serfs * 34) and NM_000212.2:c.1456del (p.Cys486Alafs * 183)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940375 and CA915940376

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case58: GT60, Male, 54 years old, French/Italian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000978, HP:0002239, HP:0000225

(Epistaxis, easy bruising, GI bleeding, gingival bleeding)

CaseHPOFreeText: N/A

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: ITGB3

Variant: NM_000212.2:c.1801T>C (p.Cys601Arg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623361

gnomAD: MAF in the European (non-Finnish) population is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C

Supplementary Table S1 & S2 Proband and Variant Information:

Case65: GT68, Male, 62 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Occasional spontaneous bleeding and frequency decreased with age

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 "LR deletion" which is the only specification we are given

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290950376

gnomAD: MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C

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

Case3: GT-3, Male, Catalan, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected sisters (GT-1) and (GT-2)

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421

(Epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Standard glycoprotein analysis confirmed the absence of αIIbβ3 in their platelets but while western blotting failed to reveal αIIb, residual β3 was at about 10% of usual levels and of normal migration (illustrated for GT1 in supplemental Figure 1).

PlateletAggregation: Platelets of all 3 patients failed to aggregate in response to a range of physiologic agonists but were agglutinated by ristocetin. Clot retraction was also defective.

CasePreviousTesting: Screened ITGA2B and ITGB3 genes of all three probands. Direct sequencing of all coding regions and splice sites of ITGA2B (30 exons) showed mutation.

Gene: ITGA2B

Variant: NM_000419.3:c.131G>T and NM_000419.3:c.1440-13_1440-1del

LegacyVariant: (p.Gly13Val)

ClinVar: N/A

CAiD: CA399806881 and CA913184940

gnomAD: N/A

Case2: GT-2, Female, Catalan, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Affected sister (GT-1) and brother (GT-3)

ParentalGenotype: N/A

CasePresentingHPOs: HP:0011891

(Post-partum hemorrhage)

CaseHPOFreeText: N/A

CaseNotHPOs:

CaseNotHPOsFreeText:

ProteinExpression: Standard glycoprotein analysis confirmed the absence of αIIbβ3 in their platelets but while western blotting failed to reveal αIIb, residual β3 was at about 10% of usual levels and of normal migration (illustrated for GT1 in supplemental Figure 1).

PlateletAggregation: Platelets of all 3 patients failed to aggregate in response to a range of physiologic agonists but were agglutinated by ristocetin. Clot retraction was also defective.

CasePreviousTesting: Screened ITGA2B and ITGB3 genes of all three probands. Direct sequencing of all coding regions and splice sites of ITGA2B (30 exons) showed mutation.

Gene: ITGA2B

Variant: NM_000419.3:c.131G>T and NM_000419.3:c.1440-13_1440-1del

LegacyVariant: (p.Gly13Val)

ClinVar: N/A

CAiD: CA399806881 and CA913184940

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case8: GT8, Male, 9 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.1651C>T (p.Arg551Trp) and NM_000419.3:c.2236G>T (p.Glu746Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399802348 (p.Arg551Trp) and CA399798321 (p.Glu746Ter)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case38: GT38, Female, 23 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:0000132

(Bruising, purpura, ecchymosis, menorrhagia)

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 and ITGB3

Variant: NM_000419.3:c.2613del in ITGA2B (p.Leu872Cysfs*38) and NM_000212.2:c.1646G>C in ITGB3 (p.Cys549Ser)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940594 (p.Leu872Cysfs*38) and CA400030198 (p.Cys549Ser)

gnomAD: MAF of (p.Cys549Ser) in the East Asian population: 0.00005453 https://gnomad.broadinstitute.org/variant/17-45369890-G-C

Supplementary Tables 1 and 2 combined information:

Case33: GT33, Female, 12 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Not available per supplementary table 1

ParentalGenotype: Parents are 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 a small response to ADP, no response to 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: ITGB3

Variant: NM_000212.2:c.719G>A (p.Arg240Gln)

LegacyVariant: N/A

ClinVar: 13553

CAiD: CA123224

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case31: GT31, Female, 13 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 and ITGB3

Variant: NM_000419.3:c.1022C>T (p.Ala341Val) in ITGA2B and NM_000212.2:c.412G>A (p.Val138Met) in ITGB3

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399804629 (p.Ala341Val) and CA400021826 (p.Val139Met)

gnomAD: N/A

Supplementary Tables 1 and 2 combined information:

Case23: GT23, Female, 11 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Not available per supplementary table 1

ParentalGenotype: Parents are consanguineous, no other genotype information available

CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0000132

(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry

PlateletAggregation: Platelet aggregation showed a small response to ADP, no response to 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: ITGB3

Variant: NM_000212.2:c.1980C>A (p.Tyr660Ter) and NM_000212.2:c.2147G>T (p.Gly716Val)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400032983 (p.Tyr660Ter) and CA400033923 (p.Gly716Val)

gnomAD: N/A

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

Case30: (GT31) 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: ITGB3

Variant: NM_000212.2:c.887_901del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA626379036

gnomAD MAF in the South Asian population is 0.00003266 https://gnomad.broadinstitute.org/variant/17-45364541-AATGACGGGCAGTGTC-A

Case6: (GT12) Gender, age and ethnicity 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: ITGA2B

Variant: NM_000419.3:c.641T>C (p.Leu214Pro)

LegacyVariant: N/A

ClinVar: 2901

CAiD: CA115848

gnomAD N/A

Case26: (GT20) Gender, age and ethnicity are not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Brother is homozygous for the mutation and the second brother is heterozygous

ParentalGenotype: Mother and father are heterozygous for the mutation

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: ITGA2B

Variant: NM_000419.3:c.1424_1427dup

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8603099

gnomAD MAF in the South Asian population is 0.0001960 https://gnomad.broadinstitute.org/variant/17-42457979-C-CACCT

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

Case18: (GT-20) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT15-GT19 are related to GT-20 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (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: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

Case17: (GT-19) Male, carrier status, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT15-GT20 are related to GT-19 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not available on bleeding phenotype/severity (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: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

Case53: (GT-72) Gender, age, or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Information not given (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: ITGB3

Variant: NM_000212.2:c.662C>T (p.Thr221Met)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623017

gnomAD: MAF in European Finnish population 0.0001386 http://gnomad.broadinstitute.org/variant/17-45363673-C-T

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

Case14: (GT-16) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT15-GT20 are related to GT-16 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Severe (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: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

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

Case42: (GT-52) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT49-GT52 are related

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: ITGB3

Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623443

gnomAD: MAF in East Asian population: 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T

Case41: (GT-51) Female, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT49-GT52 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: ITGB3

Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623443

gnomAD: MAF in East Asian population: 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T

Case11: (GT-13) Male, carrier, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Probands GT11 -GT14 are related to GT-13 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: 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: ITGB3

Variant: NM_000212.2:c.727G>C (p.Asp243His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023600

gnomAD: N/A

Supplementary Table S1:

Case26: GT30, "USA"-what the supp table states, 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: ITGB3

Variant: NM_000212.2:c.777+1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623036

gnomAD: MAF in the Latino population is 0.0006774 https://gnomad.broadinstitute.org/variant/17-45363789-G-A

Supplementary Table S1:

Case59: GT69, French, age and gender are 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.1878G>C (p.Gln626His/ p.Asp585_Gln626del)

LegacyVariant: N/A

ClinVar: 2903

CAiD: CA115852

gnomAD: N/A

Supplementary Table S1:

Case14: GT15, French, gender and age are 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.2095-19T>A and NM_000419.3:c.2770C>T

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940312 and CA399792054

gnomAD: N/A

Supplementary Table S1:

Case37: GT43a, Morrocco, 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: ITGB3

Variant: NM_000212.2:c.614+1G>T and NM_000212.2:c.683G>A (p.Arg228His)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400023344 and CA8623025

gnomAD: MAF in the African population is 0.00008012 https://gnomad.broadinstitute.org/variant/17-45363694-G-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:

Case1: GT1, French/African, Gender or 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: ITGB3

Variant: NM_000212.2:c.1913+1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400032825

gnomAD: N/A

Supplementary Table S1:

Case11: GT12, 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: ITGB3

Variant: NM_000212.2:c.565C>T (p.Pro189Ser)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA291224669

gnomAD: MAF in the European (non-Finnish) population is 0.00002638 https://gnomad.broadinstitute.org/variant/17-45362012-C-T

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

Case25: Patient CD, 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_000212.2:c.1801T>C

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623361

gnomAD: MAF in the European non Finnish population is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C

Case5: Patient DRP, 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: This variant has a typo in the paper the real variant is this: NM_000419.3:c.800 G>A and NM_000419.3:c.2930del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399805147 and CA915940386

gnomAD: N/A

Case20: Patient LPR, 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: ITGB3

Variant: NM_000212.2:c.355C>T and NM_000212.2:c.355C>T

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8622924 and CA8623361

gnomAD: MAF in the South Asian population is 0.0001307 https://gnomad.broadinstitute.org/variant/17-45360909-C-T and MAF in the European non Finnish pop is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C

Case24: Patient CI, 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_000212.2:c.1801T>C

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623361

gnomAD: MAF in the European non Finnish population is 0.00001758 https://gnomad.broadinstitute.org/variant/17-45376784-T-C

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

Case1: Male, now deceased

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0002239

(Gastrointestinal bleeding)

CaseHPOFreeText: Severe bleeding when young

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: Minimal information, not specific at all

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.1413C>G (p.Tyr471Ter) Codon change confirmed from PMID: 20492470 and NM_000419.3:c.1882C>T (p.Arg628Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290950376 and CA399801310

gnomAD: MAF in European non Finnish population 0.000008791 http://gnomad.broadinstitute.org/variant/17-42457994-G-C and MAF in Latino population 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A

Case22: Female, 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: ITGB3

Variant: NM_000212.2:c.166-2A>G (IVS2-2A>G)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA291224483

gnomAD: N/A

Case21: Male, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mild bleeding tendency (See Table 1 for Clinical and Biological data for selected genotyped patients

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.2421G>A (p.Trp807Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399796017

gnomAD: N/A

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

Case3: Patient MU, gender age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. 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 transfusion. See Table 1.

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 6

PlateletAggregation: See Table 6

CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries

Gene: ITGA2B

Variant: NM_000419.3:c.641T>C (p.Leu214Pro)

LegacyVariant: N/A

ClinVar: 2901

CAiD: CA115848

gnomAD: N/A

Case17: Patient LH, gender, age and ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: Child is patient LN, significant other is patient LB

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. 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 transfusion. See Table 1.

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 6

PlateletAggregation: See Table 6

CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries

Gene: ITGA2B

Variant: NM_000419.3:c.3062T>C

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399787956

gnomAD: N/A

Case1: Female, 3 year old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: An analysis of family members indicated that the Gln517Stop and Arg553Stop mutations were located on different alleles and inherited from the patient’s mother and father, respectively

CasePresentingHPOs: HP:0004406, HP:0002248, HP:0000978, HP:0000225

(Recurrent epistaxis, hematemesis, easy bruising, gingival bleeding)

CaseHPOFreeText: Petechial hemorrhages

CaseNotHPOs: HP:0001945, HP:0002014, HP:0005261

Fever, diarreah, hemarthrosis

CaseNotHPOsFreeText: N/A

ProteinExpression: A flow cytometry evaluation revealed marked reduction in glycoprotein IIb/IIIa (See Table 1 for Patient's Lab results)

PlateletAggregation: Patients platelets did not aggregate in response to ADP, epinephrine, arachidonic acid, or collagen but platelets had normal ristocetin induced aggregation

CasePreviousTesting: Molecular genetic analysis of ITGA2B was performed which revealed mutations

Gene: ITGA2B

Variant: NM_000419.3:c.1642C>T (p.Gln548Ter) and NM_000419.3:c.1750C>T (Arg584Ter)

LegacyVariant: Gln517Ter and Arg553Ter

ClinVar: 2892

CAiD: CA399802364 and CA115834

gnomAD: MAF in the East Asian population is 0.0002176

Case17: (M9) Female, 69 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

Case2: (GT2) Male, 76 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

ProteinExpression: <5% surface expression levels of αIIbβ3

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: ITGB3

Variant: NM_000212.2:c.1260G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8623200

gnomAD MAF in the African population is 0.00004005 https://gnomad.broadinstitute.org/variant/17-45368454-G-A

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

Case6: (GT6), Male, 82 years old, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

ProteinExpression: 40-55% surface expression levels of αIIbβ3

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: ITGB3

Variant: NM_000212.2:c.665T>C (p.Leu222Pro) and NM_000212.2:c.1871G>A (p.Cys592Tyr)

LegacyVariant: (p.Leu196Pro) and (p.Cys624Tyr) (The paper gives legacy and current nomenclature)

ClinVar: N/A

CAiD: CA291224887 and CA400032726

gnomAD MAF in the European (non-Finnish) population is 0.00006482 https://gnomad.broadinstitute.org/variant/17-45363676-T-C

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

Case3: Male, Israeli-Arab, (age is either 10 or 14)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Fig 1C for pedigree

ParentalGenotype: See Fig 1C for pedigree

CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000967

(Severe epistaxis, ecchymosis, petechiae)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: No surface expression of αIIbβ3 was found in patients’ platelets (See Fig 3)

PlateletAggregation: Absent platelet aggregation in response to ADP, epinephrine, collagen and normal ristocetin-induced platelet agglutination

CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the aIIb and B3 genes were amplified by PCR using primers

Gene: ITGA2B

Variant: NM_000419.3:c.97A>G (p.Asn2Asp)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399806951

gnomAD: N/A

Case9: Patient CC

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs:

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: αIIbβ3 expression

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.666C>A (p.Phe222Leu)

LegacyVariant: (p.Phe191Leu)

ClinVar: N/A

CAiD: CA399805465

gnomAD: N/A

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

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

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

Case9: Patient ID I, Female, 3 years old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Related to Patient's J and K (See Table 1)

ParentalGenotype: N/A (Parents are consangenous)

CasePresentingHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0004406

(Petechiae, purpura, easy bruising, recurrent epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000225, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

(Gingival bleeding, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)

CaseNotHPOsFreeText: Hemorrhage after dnetal, hemorrhage after trauma, ear bleeding, hematoma

ProteinExpression: N/A

PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin

CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.

Gene: ITGA2B

Variant: NM_000419.3:c.1652G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8602986

gnomAD: MAF in South Asian population is 0.00006536 http://gnomad.broadinstitute.org/variant/17-42457470-C-T

PreviouslyPublished: PMID: 19172520

Case15: GT04, Female, India, age of onset is 11 years old

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: Menorrhagia HP:0000132

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: ITGB3

Variant: NM_000212.2:c.262C>T (p.Arg88Ter) and NM_000212.2:c.356G>A (p.Arg119Gln)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400020703 and CA8622925

gnomAD: MAF in the Other population is 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T and MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A

Case16: GT07, Male, India, age of onset is 3 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: ITGB3

Variant: NM_000212.2:c.153del (p.Trp51CysfsTer5)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940728

gnomAD: N/A

Case34: GT55, Male, India, age of onset is 21 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: ITGB3

Variant: NM_000212.2:c.921C>A (p.Tyr307Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400025209

gnomAD: N/A

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

Case29: GT40, Female, India, age of onset is 6 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: ITGB3

Variant: NM_000212.2:c.428T>G (p.Leu143Trp)

LegacyVariant: N/A

ClinVar: 13567

CAiD: CA123252

gnomAD: MAF in the Other population is 0.0001629 https://gnomad.broadinstitute.org/variant/17-45361875-T-G)

Case18: GT09, Female, India, age of onset is 21 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: ITGB3

Variant: NM_000212.2:c.428T>G (p.Leu143Trp) and NM_000212.2:c.1261G>A (p.Val422Met)

LegacyVariant: N/A

ClinVar: 13567

CAiD: CA123252 and CA400028437

gnomAD: MAF in the Other population is 0.0001629 https://gnomad.broadinstitute.org/variant/17-45361875-T-G

Case1: Male, 18 years old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 4 for family pedigree of patients carrying the 288delC mutation in GPIIb

ParentalGenotype: Heterozygous for variant

CasePresentingHPOs: HP:0000978 (Bruising)

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis shown in Fig 1

PlateletAggregation: Platelets failed to aggregate either spontaneously or in response to ADP, adrenaline, collagen or arachidonic acid, but they showed agglutination in the presence of ristocetin

CasePreviousTesting: ITGA2B and ITGB3 both were sequenced

Gene: ITGA2B

Variant: NM_000419.3:c.291del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940464

gnomAD: N/A

Case2: Female, 67 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.1063G>A (p.Glu355Lys)

LegacyVariant: (p.Glu324Lys)

ClinVar: 2899

CAiD: CA115844

gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T

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

Supplemental Table S1:

Case12: Male, Italy, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: Moderate bleeding

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: <5% αIIbβ3 expression

PlateletAggregation: Absent platelet aggregation (all the information that is provided in Supp. Table S1)

CasePreviousTesting: Sanger sequencing of exons, splice sites and untranslated regions of the ITGA2B and ITGB3 genes was performed

Gene: ITGA2B

Variant: NM_000419.3:c.1742C>A (p.Ala581Asp)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399802112

gnomAD: N/A

PreviouslyPublished: PMID: 12083483

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