Case#: Case 2, 20 yo Female

DiseaseAssertion: Glanzman thrombasthenia

ParentalGenotype: Not provided

CasePresentingHPOs: (HP:0000978, Bruising susceptibility) (HP:0000421, Epistaxis)

PlateletAggregation: Strong reduction of platelet aggregation with all agonists, except ristocetin. Normal platelet count.

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

ProteinExpression: Flow cytometry, platelets with 18% to 24% residual αIIbβ3

CasePreviousTesting: Not provided

PreviouslyPublished: Not provided

Gene: ITGB3

HGVS: NM_000212.3:c.187C>T

ClinVar: 631774 https://www.ncbi.nlm.nih.gov/clinvar/variation/631774/

CAID: CA8622892

gnomAD: PopMax = 0.00002555 https://gnomad.broadinstitute.org/variant/17-47283375-C-T?dataset=gnomad_r4

Gene: ITGB3

HGVS: NM_000212.3:c.505C>T

ClinVar: 953061 https://www.ncbi.nlm.nih.gov/clinvar/variation/953061/

CAID: CA291224658

gnomAD: PopMax = 2.800e-7 https://gnomad.broadinstitute.org/variant/17-47284586-C-T?dataset=gnomad_r4

Case#: Male, 20

DiseaseAssertion: Glanzmann thrombasthenia–like syndrome

FamilyInfo: Twin brother (shares variant), Mother, Figure 1B

ParentalGenotype: Maternal inheritence, diagnosed GTLS

CasePresentingHPOs: thrombocytopenia (HP:0001873), Platelet anisocytosis (HP:0032438), (HP:0003645) activated partial thromboplastin times, (HP:0000967) petechia

PlateletAggregation: Thrombocytopenia (51×109/L, reference interval (RI): 150–450×109/L), Serum antiplatelet antibody test was negative. Platelet macrocytosis.

CaseHPOFreeText: Occasional petechia noted. Platelet macrocytosis.

CaseNotHPOs: (HP:0012200) prothrombin, (HP:0001892) abnormal bleeding

CaseNotHPOFreeText: Platlets in Figure 1A. No thrombotic symptoms.

ProteinExpression: this mutation entails the substitution of the hydrophobic leucine with a hydrophilic arginine. This charge reversal in the TMD of β3 may potentially impact helix conformation, integrin assembly, and signaling pathways.Platelet aggregation was severely diminished in response to adenosine 5′-diphosphate, collagen, arachidonic acid, and epinephrine, but not ristocetin, Figure 1E. Flow cytometry showed slightly increased CD41a expression, probably because of increased platelet size, Figure 1F.

CasePreviousTesting: Exome sequencing via TruSight One expanded panel (Illumina), whole-genome sequencing via the Korean National Project of Bio Big Data, Maternal inheritance was confirmed via Sanger sequencing analysis.

PreviouslyPublished: NA

Gene: ITGB3

Variant: NM_000212.3: c.2192T>G, [NP_000203.2:p.Leu731Arg]

HGVS: NM_000212.3:c.2192T>G (ITGB3)

ClinVar: Absent

CAID: CA400034083

gnomAD: Absent

Case#: Female, at birth

DiseaseAssertion: Glanzmann Thrombasthenia

FamilyInfo: Figure 1 Consanguinity Mother: 27 yo. Positive for mutation. Epistaxis, hypochromic microcytic anemia, cesarean postoperative vaginal bleeding. Maternal aunt present with GT, Positive for mutation. Maternal cousin present with GT, Positive for mutation. Paternal cousins present with GT, Positive for mutation.

ParentalGenotype: Both parents heterozygous carriers.

CasePresentingHPOs: HP:0000978, Bruising susceptibility. HP:0000225, Gingival bleeding. HP:0003265, Neonatal hyperbilirubinemia. HP:0011869, Abnormal platelet function. HP:0004887, Respiratory failure requiring assisted ventilation. HP:0000967, Petechiae.

PlateletAggregation: Normal coagulation. Reduced platelet function.

CaseHPOFreeText: APGAR score 9. Spontaneous skin bruising. Started on feeds second day of life.

ProteinExpression: Platelet function assays showed severely reduced activity.

Gene: ITGB3

Variant: p.Asp145Asn

HGVS: NP_000203.2:p.Asp145Asn

ClinVar: 627066

CAID: CA400021939

gnomAD: Absent