Case#: 3 month old male neonate

Disease: Glazmann's Thrombasthenia

CasePresentingHPOs: HP:0000967, HP:0007420, HP:0003010

Petechiae, Spontaneous hematomas, Prolonged bleeding time

PlateletAgreggation: Impaired in response to all stimuli including adenine diphosphate (2%), collagen (24%), arachidonic acid (13%), and epinephrine (13%). In contrast, platelet aggregation to ristocetine was almost normal (67%; lower limit of normal is 70%).

ExpressionEvidence: Flow Cytometry analysis showed reduced αIIbβ3 expression on patient platelets

FamilyInfo: Pedigree Figure 1. Homozygous HPA-1aa father and heterozygous HPA-1ab mother indicating that both HPA-1a alleles inherited to the GT son are defective carrying either Cys460Trp or Trp11Arg mutation.

GenotypingMethod:

Compound heterozygous:

Allele 1

ClinVar: 953012

CAID: CA400029369

Variant: NM_000212.3:c.1458C>G

GnomAD: Not Found

FunctionalEvidence: Flow cytometry analysis of wild-type (Cys460) and mutant (Trp460) expressed on HEK293 cells showed equal surface expression of αIIbβ3 and αvβ3. Immunoblotting analysis (Figure 2B) showed that the mutant β3 migrated slightly slower in comparison with wild-type β3 isoform, indicating that the disruption of one disulfide bond due to Cys460Trp mutation alters the secondary structure of integrin αIIbβ3. However, evidence that Csy460Trp mutation alters the binding of some mAbs against HPA-1a.

Allele 2:

ClinVar: 953028

CAID: CA291240306

Variant: NM_000212.3:c.31T>C

GnomAD: Not Found

Supplementary Table S1:

Case53: GT62, 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: ITGB3

Variant: NM_000212.2:c.31T>C (p.Trp11Arg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA291240306

gnomAD: N/A