Case: IP-5

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <1%, VWF:RCo <6% and FVIII:C 2,4%. Epistaxis, oral cavity bleedings, gastrointestinal bleedings and hematomas.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: deletion of exons 4-34

HGVS:

ClinVarID:

CAID:

gnomAD:

Case: IP-2

DiseaseAssertion: VWD3

FamilyInfo: The mother reported no history of bleeding episodes and the laboratory data were in the border line of the normal range.

ParentalGenotype(s): mother is heterozygous for the p.Gln2551AlafsX16 in the VWF gene

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <6%, VWF:RCo <6% and FVIII:C 2%. Clinically, repetitive severe epistaxis and subcutaneous hematomas were observed.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany).

PreviouslyPublished: NA

Gene: VWF

Variant: p.Gln2551AlafsX16

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: VWF

Variant: whole gene deletion

ClinVarID or CAID:

gnomAD:

Case#: 03044, Age 27, Female (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #03230

Parental Genotype: not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 22, VWF:RCo:18, FVIIIC:29, VWF:CB: 17

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: c.6699_6702dup (p.Cys2235ArgfsTer8)

ClinVar:

CAID:

gnomAD:

Case#: 21011, Age 54, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2111.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NP_000543.2:p.Ser83Ter (c.246_247insT)

ClinVar: N/A

CAID: PA1139532036 CAID

gnomAD: N/A

Case#: 36004, Age 69, Female, Blood Type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3603.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 22, VWF:RCo:18.5, FVIII:C: 19, VWF:CB: 19

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2546+55G>T (p.=)

ClinVar: N/A

CAID: N/A

gnomAD: N/A

PMID: 28971901

Gene: von Willebrand Disease (VWF)

Case:44‐year‐old male patient

DiseaseAssertion:type 3‐VWD patient

FamilyInfo:positive family hsiory: The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL)., NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister

ParentalGenotype(s):VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in father, but mother not tested

CasePresentingHPOs:BAT score=16, Arterial thrombosis=ischemic stroke, FVIII:C*=1, VWF:Ag=3, Proein S:58, Protein C:100, antithrombin III=106, activated protein C resistance:2.9. CaseHPOFreeRext: Complete blood count showed normocytic anemia (hemoglobin 74 g/L), normal white cell (and differential), and platelet counts. He had prolonged activated partial thromboplastin time (APTT) (89.4 s (s) [reference range (RR), 28.0–44.0 s]) with greatly decreased FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) (Table 1). Abdominal ultrasound scanning revealed fatty liver, normal gallbladder, spleen, pancreas, and kidneys. Four hundred ml of virus inactivated fresh frozen plasma (FFP) was transfused, and his VWF:Ag increased to 6 IU/dL. On Day 2 after admission, the patient abruptly experienced numbness and weakness in his right limb.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:n.a

GenotypingMethod:NGS

PreviouslyPublished: If applicable.

Gene: VWF

Variant:c.2328delT (p.A778Lfs*23) and c.6521G > T (p.C2174F)

HGVS:n.a.

ClinVarID:n.a.

CAID:n.a.

gnomAD: n.a.

PMID: 24924395

Gene: MYH7

"RSD had a significant antihypertensive effect and inhibited hypertensive-induced cardiac hypertrophy in SHRs and showed advantages compared with ACEI in decreasing BP in the early stage and in inhibiting myocardial fibrosis"

Case#: Subject number 18, female, 40 years (diagnosis), 65 years (baseline visit), 64 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 13, male, 43 years (diagnosis), 47 years (baseline visit), 45 years (ERT), 44 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 21, female, 20 years (diagnosis), 52 years (baseline visit), 45 years (ERT), 39 (age at ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 8, female, 49 years (diagnosis), 59 years (baseline visit), 52 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 1, female, 38 years (diagnosis), 50 years (baseline visit), 47 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: No mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 31, male, 49 years (diagnosis), 51 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 10, male, 13 years (diagnosis), 42 years (baseline visit), 39 years (ERT), 38 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 19, female, 24 years (diagnosis), 35 years (baseline visit), 29 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 34, female, 28 years (diagnosis), 39 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), HP:0003236 (Elevated circulating creatine kinase concentration)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 17, male, 14 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 22, male, 47 years (diagnosis), 64 years (baseline visit), 57 years (ERT), 56 (age at ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 16, male, 22 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 6, female, 36 years (diagnosis), 51 years (baseline visit), 47 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 28, male, 20 years (diagnosis), 43 years (baseline visit), 43 (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 23, male, 2 years (diagnosis), 8 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 33, female, 16 years (diagnosis), 20 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 6, male, 4 months (onset), 4 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: "no family history of neuromuscular disorders"

CasePresentingHPOs: HP:0004887 (respiratory failure requiring assisted ventilation), HP:0001639 (hypertrophic cardiomyopathy), HP:0001522 (death in infancy), HP:0002090 (pneumonia)

CaseHPOFreeText: infantile-onset, dysphagia at baseline

CaseNotHPOs:

CaseNotHPOFreeText: no tracheostomy, not on BiPAP

CasePreviousTesting: “GAA activity in peripheral blood leukocytes lower than normal”; on enzyme replacement therapy

Case#: Subject number 2, male, 20 months (onset), 24 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: Patients 2 and 3 are full siblings

CasePresentingHPOs: HP:0002355 (difficulty walking), HP:0002205 (recurrent respiratory infections), HP:0004887 (respiratory failure requiring assisted ventilation)

CaseHPOFreeText: on BiPAP, ambulatory (transport ventilator), juvenile-onset, assistive device (wheelchair)

CaseNotHPOs:

CaseNotHPOFreeText: no dysphagia at baseline, no tracheostomy

CasePreviousTesting: “GAA activity in peripheral blood leukocytes lower than normal”; on enzyme replacement therapy

PMID: 31392189

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case1: Patient KW (this patient can be found in the GT database)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225

(Epistaxis, gingival bleeding)

CaseHPOFreeText: Blood transfusions needed

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Surface expression of GPIIb/GPIIIa not reported for this patient

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: 4.5-KB DEL, EX2-9

LegacyVariant: N/A

ClinVar: 2890

CAiD: N/A

gnomAD: N/A

PreviouslyPublished: PMID: 1702098

Case5: (GT34), Gender, age and ethnicity not reported

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: NC_000017.11:g.44393555C>T (g.951G>A promoter variant)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913189168

gnomAD N/A

Case10: Female, 12 years old, Tamil Nadu India

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0006298

(Gingival bleeding, prolonged bleeding after dental extraction)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 1 for values

PlateletAggregation: See Table 1 for values

CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

Gene: ITGB3

Variant: 330_336TCCCCAGdel is not showing up in CAR noting it as Unregistered

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered

gnomAD: N/A

Case1: Male, 9 years old,

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: One brother, with no signs of bleeding diathesis

ParentalGenotype: Father is heterozygous for the c.2268C>T mutation and the mother is compound heterozygous with the c.2268C>T variant and c.2330C>T variant

CasePresentingHPOs: HP:0000421 Epistaxis

CaseHPOFreeText: Submucosal bleeding, hematomas, excessive achilles tendon bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: The patient's αIIbβ3 receptor count was estimated approximately 50% of that measured in a healthy age-matched control by quantitative flow cytometry

PlateletAggregation: Complete absense of platelet aggregation in response to ADP, arachidonic acid, epinephrine, collagen

CasePreviousTesting: Direct sequencing of the patients αIIb and β3 genes was perforemed

Gene: ITGB3

Variant: NM_000212.2:c.2248C>T (p.Arg750Ter)

LegacyVariant: (p.Arg724Ter)

ClinVar: 13564

CAiD: CA123246 (p.Arg750Ter)

gnomAD: N/A

Case19: (GT-21) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT-22 is related to GT-21 see Table 1

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

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.2302-1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400034626

gnomAD: N/A

Case1: Female, 35 day old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: The proband’s mother and father carry heterozygous c.512delC and c.1686delG mutations, respectively. Other parameters for parents are shown in Table 1.

CasePresentingHPOs: HP:0031364, HP:0000967

(Ecchymosis, petechiae)

CaseHPOFreeText: Large parietal and cervical cephalohaematoma, severe anemia

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry of platelet surface antigens revealed the absence of the αIIbβ3 complex.

PlateletAggregation: Prolonged closure time at PFA-100, absent ADP, adrenaline, collagen induced platelet aggregation, and ristocetin induced platelet aggregation at the lower limit of normal

CasePreviousTesting: Sequencing of ITGA2B and ITGB3 genes showed that proband is compound het.

Gene: ITGA2B

Variant: Can not conclusively determine if c.481delC and c.1654delG are the variants intended by the authors based on the available information.

LegacyVariant: N/A

ClinVar: N/A

CAiD: N/A

gnomAD: N/A

Case5: Patient ID E, Female, 1 year old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978, HP:0000225

(Easy bruising, gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

(Petechiae, purpura, recurrent epistaxis, GI bleeding, Intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)

CaseNotHPOsFreeText: Hemorrhage after dental, 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 a;; 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: c.1460insAGGT (p.Ser477Gfs*111)

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered Variant

gnomAD: N/A

PMID: 12837870

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

PMID: 21930696

Gene: DLD

Disease: Pyruvate dehydrogenase E3 deficiency

MonDO: MONDO:0009529

InheritancePattern: Autosomal recessive

PMID: 17945527

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

Gene: NAT8L

Disease: NAA deficiency

MonDO: MONDO:0013549

PMID: 19807691

PMID: 10915611

Gene: DBT

Disease: Maple syrup urine disease

MonDO: MONDO:0009563

InheritancePattern: AR

PMID: 32360764

Variant NM_000280.5:c.333C>A(p.Val111=)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Notes Proband with confirmed aniridia and confirmed de novo appearance of the variant, summary in table 1, proband information in the "splice variant" section. It is noted however that the authors do not include the parental genotype or phenotype data.

Clinical Lab The Wessex Regional Genetics Laboratory has been contacted for variants c.333C>A and c.1183G>C, there is no additional information than what is in the table and if familial or de novo is claimed it is because parental samples were collected and tested negative for the variant in the published proband

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The proband reported has clinical features of neurofibromatosis, with a de novo donor splice site variant in NF1, as well as a 12-bp deletion in RAB39B, which the authors assert was responsible for the phenotypes of severe ID, behavioral problems and aggressiveness.

CaseID D

VariantInPub IVS2+9G>A

MANE NM_001368894.2:c.-129+9G>A

Zygosity heterozygous

PhenotypesProband HP:0000568, HP:0000482, HP:0000518, HP:0000639, HP:0000647, HP:0000491

FamilyInfo No family or segregation information was included

SpliceFormVariant No RT-PCR or northern blot to confirm the intronic substitution lead to a splice variant

PMID 22830481

Disease Pulmonary fibrosis/ bone marrow failure syndrome

GroupPresentingHPOs: only shared phenotype was reduced GALNS activity in leukocytes

GroupGenotypingMethod: Sanger seq of amplified exons

NumberMales: 15

NumberFemales: 6

NumberFamilies: 19

CountryOrigin: China

AgeRange: 1yo to 7.8yo

TotalNumber: 21

FamilyInfo:19 families, siblings P1 and P2, P3 and P4, parents were studied for segregation info

VariantCount: 15

Linking DKC with Pulmonary disease

PMID: 8829629

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID 30291432

MONDO MONDO:0800183

Notes minigene splicing assay for c.-128-2del that shows majority of transcript is one where exon 3 is skipped with some but greatly reduced canonical transcript levels

Family#PresentingHPOs: None

FamilyNotHPOs: Free of clinical phenotypes

CountryOrigin: China

Ethnicity: Chinese

Race: east Asian

Family#GenotypingMethod: Whole exome sequencing

Affected: None reported

Unaffected: mother and maternal grandmother carriers of same allele, father carrier for separate allele

Segregations: 2?

PublishedLOD: N/A

eLOD: too few segregations

AddSegregationInfo:

ProbandLabel: Ma_Proband

Variant: Maternal - NM_000512.5:c.1288C>G Paternal - NM_000512.5:c.1156C>T

ClinVar:

CAID:

gnomAD:

FamilyAddInfo: paternal allele is previously reported as pathogenic, maternal allele and has only been reported in one proband/family

FamilyPMIDs: 34557487

PMID 15814878

Variant NM_198253.3:c.3268G>A

Gene TERT

PMID: 16713582

Gene: ELP1

Disease: Familial dysautonomia

MonDO: MONDO:0009131

InheritancePattern: AR

Notes: Functional Alteration

PMID 28862745

Gene: VPS13C

Disease Parkinson disease 23, autosomal recessive, early onset

MonDO: MONDO:0014796

InheritancePattern: AR

PMID: 33364235

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

NonHumanModel: Niu_Mouse

GeneAlteration: Transcription activator like effector nuclease (TALEN) - mediated strategy was used to target exon 1 of RAB39B to generate the knockout mice in the C57BL/6J background. A mouse line with a "GT" deletion at nucleotide 106-107 that caused a frameshift and early truncation of RAB39B was obtained. Authors confirmed absence of RAB39B loss of fucntion.

ModelPhenotype: Learning and memory deficits

HumanPhenotype: HP:0001249

ModelEvidence: 2-mo hemizygous male knock-out (KO) mice showed behavioral alterations compared to WT mice. KO mice showed reduced anxiety, impaired recognition memory, impaired short-term working memory, impaired spatial memory, impaired social novelty recognition, compromised motor skill learning, but motor ability was not affected. Authors indicate that impaired learning and memory was associated with altered synaptic plasticity.

ModelVariant:

WhereInPaper:

The evidence is scored minimal points as the phenotype recapitulated aligns with the human ID phenotype; however, the model provides no evidence of Parkinson disease phenotype. (0.5)

NonHumanModel: Mus musculus

GeneAlteration: p.Arg386Cys the most frequently reported missense variant linked as a causal pathogenic allele in mucopolysaccharidosis IVA patients

ModelPhenotype: In addition to undetectable GALNS enzyme activity in any assayed tissue, increased keratan sulfate detection in liver tissue and blood serum, the boney deformations missing from previous models were present in this mouse model HP:0004325, MP:0001258, HP:0005736

HumanPhenotype: HP:4000197, HP:0012069, HP:0004322, HP:0005736

ModelEvidence: CRISPR/Cas9 directed site mutagenesis of murine Galns coding sequence at codon homologous to the human p.Arg388Cys mutation cited in human MPSIVA patients. Mouse model showed increased keratan sulfate accumulation in liver and blood serum, undetectable n-acetylgalactosamine-6-sulfatase activity in any body tissue assayed as well as skeletal deformities consistent with human MPSIVA patients

ModelVariant: p.Arg388Cys

WhereInPaper:

PMID: 34504088

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 33390680

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case report

No genetic or enzymatic confirmation of MPSIVA

PMID 9516413

Notes discusses transactivation function of PST rich domain made up of exons 10-13

PMID 28813500

Variant c.3268G>A

Phenotypes HP:0001402, HP:0001394

Phenotypes free-text hepatocellular carcinoma, cirrhosis

PMID: 27825773

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Important citations to study how TERC relates to genetic anticipation (inheriting not only TBD genes but short telomeres to begin with, leading to earlier onset)

NonHumanModel: Zhang_Mouse

GeneAlteration: Exon 2 of RAB39B was targeted using two gRNAs and Cas9 mRNA in the C57BL/6N background. Mice harboring 397-bp deletions in exon 2 were obtained.

ModelPhenotype: HP:0000256 Social and memory deficits

HumanPhenotype: HP:0001249, HP:0000256

ModelEvidence: Similar to PMID: 33364235, authors show through ASD-related tests that KO mice exhibit social and memory deficits. They also show that RAB39B variation results in over-proliferation and differentiation deficits of neural progenitor cells, which results in larger that normal number of neurons. Mice therefore have macrocephaly.

ModelVariant:

WhereInPaper:

The model is scored reduced points as the mice recapitulate the ASD phenotype seen in some human patients with RAB39B variants, but does not provide evidence for the Parkinson disease phenotype. (0.5)

PMID 22079513

Disease Idiopathic pulmonary fibrosis

PMID: 33397040

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 21103895

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 34628056

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: N/A

Reference: Daniele S., Pelliccioli G.P., Daniele C., Mandich P., Montera M., Simoncelli C., et al (1996). Von Hippel-Lindau disease in twins: Clinical and molecular study. European Journal of Neurology, 3(6), 581-587. https://doi.org/10.1111/j.1468-1331.1996.tb00276.x

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9156047

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 20447124

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 29941223

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9497878

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 27057652

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 25952756 Gene: VHL StandardizedReferenceSequence: NM_000551.3

PMID: 32900738

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 11685621

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 18928468

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 24112165

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 10592114

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 35269902

Gene: F9

HGNC: 3551

PMID: 10874302

Gene: F9

HGNC: 3551

PMID: 34626083

Gene: F9

HGNC: 3551

PMID: 8680410

Gene: F9

HGNC: 3551

PMID: 10647899

Gene: F9

HGNC: 3551

PMID: 2198809

Gene: F9

HGNC: 3551

PMID: 2738071

Gene: F9

HGNC: 3551**

PMID: 31361134

Gene: F8

No Evidence: This article does not mention F8 or Hemophilia A.

PMID: No PMID (chrome-extension://bjfhmglciegochdpefhhlphglcehbmek/pdfjs/web/viewer.html?file=https%3A%2F%2Filliad.lib.unc.edu%2FNOH%2Filliad.dll%3FAction%3D10%26Form%3D75%26Value%3D3078221)

Gene: F9

HGNC: 3551

PMID: 10739381

Gene: F9

HGNC: 3551

PMID: 31277033

Gene: F8

NoEvidence: This article does not discuss Hemophilia A, F8 or blood disorders.

PMID: 8833911

Gene: F9

HGNC: 3551

PMID: 31332444

Gene: F8

InsufficientEvidence: Patients are mentioned; however, no mention of variants.

PMID: 8499919

Gene: F9

HGNC: 3551

PMID: 1579901

Gene: F9

HGNC: 3551

PMID: 29296726

Gene: F9

HGNC: 3551

PMID: 8318985

Gene: F9

HGNC: 3551

PMID: 31344171

Gene: F8

No Evidence: No variants or probands mentioned in this review of Hemophilia A

PMID: 9233593

Gene: F9

HGNC: 3551

PMID: 31430659

Gene: F8

No Evidence: This article does not mention F8, rather it discusses cytokine analysis.