Case31: Male, 41yo (at enrollment and onset)

CasePresentingHPOs: HP:0002094, HP:0003701, HP:0003327, HP:0003236, HP:0002098, HP:0002111, HP:0003458, HP:0100284

HPOsFreeText: asymmetric weakness of extremities, CK = 573 IU/L, required use of ventilator, FVC = 33.7%, unspecific myopathic changes present in muscle pathology, DBS GAA activity = .05, mixed leukocyte GAA activity = 1.40

CaseNotHPOs: HP:0001627

NotHPOsFreeText:

CaseAddInfo:

CasePreviousTesting: clinical history, laboratory data, DBS and ML assays to measure GAA activity, electromyography, muscle pathology analysis

CaseGenotypingMethod: full sequencing of GAA gene

VariantAllele1: NM_000152.3:c.1822C>T

CAID: CA8815488, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1822C%3ET

gnomAD: 0.00001806, http://gnomad.broadinstitute.org/variant/17-78086444-C-T

VariantAllele2: NM_000152.4(GAA):c.2238G>C (p.Trp746Cys)

ClinVar: 265160, https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: 0.0002987, http://exac.broadinstitute.org/variant/17-78090815-G-C

Case#: Subject number 30(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

glucosidase activity: GAA activity #2 (NBS) 1.07 in dried blood spots (>2.10 micromole/L/h is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 12(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 464 U/L (60-305 U/L is normal)

glucosidase activity: 2.60 in confirmatory testing (>3.88 is normal). AST: 112 (22–71); ALT: 50 (7–50)

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.2238G>C

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 3(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 125 U/L (28-300 U/L is normal), AST: 56 U/L (24-72 U/L is normal), ALT: 49 U/L (17-63 U/L is normal), Hex4: 4.5 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.73 micromole/L/h and GAA activity #2 (NBS) 1.08 in dried blood spots (>2.10 micromole/L/h is normal). 3.6 in confirmatory testing (>6.7 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 16(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 140 U/L (60-305 U/L is normal), AST: 73 U/L (22-71 U/L is normal), ALT: 39 U/L (7-50 U/L is normal), Hex4: 8.5 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 99.8 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 1.06 micromole/L/h and GAA activity #2 (NBS) 0.26 in dried blood spots (>2.10 micromole/L/h is normal). 6.4 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 8(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 365 U/L (60-305 U/L is normal), Hex4: 5.23 mmol/mol Creatinine (≤8.9 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 0.83 micromole/L/h and GAA activity #2 (NBS) 0.85 in dried blood spots (>2.10 micromole/L/h is normal). 0.93 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1655 T>C

Variant 2 ClinVarID: 279811

Variant 2 CAid: CA8815429

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 1(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 530 U/L (28-300 U/L is normal), AST: 72 U/L (24-72 U/L is normal), ALT: 41 U/L (17-63 U/L is normal), Hex4: 4.9 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.86 micromole/L/h and GAA activity #2 (NBS) 0.78 in dried blood spots (>2.10 micromole/L/h is normal). 3.1 in confirmatory testing (>6.7 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 15, male, 42 years (report), 15 years (onset), 23 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText: on BiPAP, ambulatory

CaseNotHPOs: HP:0009830, HP:0000360, HP:0002650, HP:0000939, HP:0000821, HP:0000365, HP:0002617, HP:0100647, HP:0010788, HP:0001638 (peripheral neuropathy, tinnitus, scoliosis, osteoporosis, hypothyroidism, hearing loss, aneurysm, Graves disease, Testicular cancer, cardiomyopathy)

CaseNotHPOFreeText: no infusion reaction, no tracheostomy

CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy

Variant 1: NM_000152.5(GAA):c.-32-13T>G (p.Tyr766Ser)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1134C>G

Variant 2 ClinVarID: 595469

Variant 2 CAid: CA401365023

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 9, female, 74 years (report), 30s years (onset), 62 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000365 (hearing loss), HP:0000360 (tinnitus)

CaseHPOFreeText: Infusion reaction, ambulatory, assistive device (cane for long distance)

CaseNotHPOs: HP:0000821, HP:0002650, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0001638 (hypothyroidism, scoliosis, aneurysm, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, cardiomyopathy)

CaseNotHPOFreeText: no tracheostomy, not on BiPAP

CasePreviousTesting: “documented deficiency of acid alpha-glucosidase enzyme activity”; on enzyme replacement therapy

Variant 1: NM_000152.5(GAA):c.-32-13T>G (p.Tyr766Ser)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.2655_2656delCG (p.Val886GlufsTer2)

Variant 2 ClinVarID: 597005

Variant 2 CAid: CA913191011

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient22: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.1241del

CAID: CA913184736, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184736

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)

ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T

Patient12: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.2585del

CAID: CA913184734, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184734

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)

ClinVar: 371481, https://www.ncbi.nlm.nih.gov/clinvar/variation/371481/

gnomAD: 1.653e-05, http://exac.broadinstitute.org/variant/17-78093082-CTG-C

Patient18: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.796C>T (p.Pro266Ser)

ClinVar: 556117, https://www.ncbi.nlm.nih.gov/clinvar/variation/556117/

gnomAD: n/a

Patient27: Female, 9 years report, 7 years onset

CasePresentingHPOs: N/A

HPOsFreeText: GAA activity 5.5% from leukocyte

CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient37: Male, 25 years report, 8 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 9% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient17: Male, 75 years report, 72 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 4.8% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient13: Male, 1 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 4.9% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient10: Male, 39 years report, 17 years onset

CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098, HP:0002240 (Cardiomegaly, Muscle weakness, Respiratory distress, Hepatomegaly)

HPOsFreeText: GAA activity 9.3% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseAddInfo: LOPD

CasePD/Pathogenic-10: 2 weeks diagnosis

HPOsFreeText: GAA activity 5.5 (nmol · h−1 · mg−1), Mean percentage of normal 7.8%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.271G>A (p.Asp91Asn)

ClinVar: 4020 https://www.ncbi.nlm.nih.gov/clinvar/variation/4020/

gnomAD: European (Non-Finnish) 0.03291, Overall 0.02049 http://gnomad.broadinstitute.org/variant/17-78078656-G-A

Variant2: NM_000152.4:c.2161G>T (p.Glu721Ter)

CAID: CA401370611 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2161G%3ET

gnomAD: Not in gnomAD

Variant3: NM_000152.4:c.2237G>T (p.Trp746Leu)

ClinVar: 284776 https://www.ncbi.nlm.nih.gov/clinvar/variation/284776/

gnomAD: European (Non-Finnish) 1.244e-4, Overall 7.798e-5 http://gnomad.broadinstitute.org/variant/17-78090814-G-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 2 and 3 are in cis

CaseLOPD-15: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.6 (nmol · h−1 · mg−1), Mean percentage of normal 5.1%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.271G>A (p.Asp91Asn)

ClinVar: 4020 http://www.ncbi.nlm.nih.gov/clinvar/variation/4020

gnomAD: European (Non-Finnish) 0.03291, Overall 0.02049 http://gnomad.broadinstitute.org/variant/17-78078656-G-A

Chromosomal code not provided

Variant2: NP_000143.2:p.V740Gfs*55

ClinVar: N/A

gnomAD: N/A

Chromosomal code not provided and typo likely

Variant3: NP_000143.2:p.T234 mol/L

ClinVar: N/A

gnomAD: N/A

CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-18: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.0%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2188G>T (p.Glu730Ter)

ClinVar: 495665 https://www.ncbi.nlm.nih.gov/clinvar/variation/495665/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

CasePD/VOUS-2: 2 weeks diagnosis

HPOsFreeText: GAA activity 16.6 (nmol · h−1 · mg−1), Mean percentage of normal 23.3%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2069C>T (p.Pro690Leu)

ClinVar: 424308 https://www.ncbi.nlm.nih.gov/clinvar/variation/424308/

gnomAD: East Asian 1.077e-4, Overall 2.337e-5 http://gnomad.broadinstitute.org/variant/17-78087045-C-T

CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-12: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.0 (nmol · h−1 · mg−1), Mean percentage of normal 2.8%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Chromosomal code not provided and typo likely

Variant2: NP_000143.2:p.V350 mol/L

ClinVar: N/A

gnomAD: N/A

CaseAddInfo: Late Onset Pompe Disease

CaseLOPD-14: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2509C>T (p.Arg837Cys)

ClinVar: 456408 https://www.ncbi.nlm.nih.gov/clinvar/variation/456408/

gnomAD: European (Non-Finnish) 4.676e-5, Overall 2.487e-5 http://gnomad.broadinstitute.org/variant/17-78092019-C-T

CaseAddInfo: Late Onset Pompe Disease

CaseLP2-10: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.06 umol/hr/L, Serum CK at 670 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.2662G>T (p.Glu888Ter)

ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

CaseOPOPD-10: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.34 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.693-5C>T

ClinVar: CA8814990 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.693-5C%3ET

gnomAD: East Asian 3.516e-4, Overall 3.900e-5 http://gnomad.broadinstitute.org/variant/17-78081351-C-T

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation

CaseOPOPD-62: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.85 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2024_2026delACA (p.Asn675del)

ClinVar: 189006 https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: East Asian 1.106e-4, Overall 8.275e-6 http://gnomad.broadinstitute.org/variant/17-78086806-CACA-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseLP2-7: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.22 umol/hr/L, Serum CK at 89 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1054C>T (p.Gln352Ter)

CAID: CA294891876 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA294891876

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

CaseOPOPD-67: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.93 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2236T>G (p.Trp746Gly)

ClinVar: 556431 https://www.ncbi.nlm.nih.gov/clinvar/variation/556431/

gnomAD: East Asian 6.410e-4, Overall 3.186e-5 http://gnomad.broadinstitute.org/variant/17-78090813-T-G

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 2 other patients have this genotype

CaseOPM-1: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.97 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation, Nomenclature indicates Variants 1 and 2 are in cis and the other allele is Wildtype

CaseIP2-6: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.02 umol/hr/L, Serum CK at 709 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates that Variant 1 and 2 are in cis and the patient is homozygous for this allele, 2 more patients also have the same genotype

Patient11: 62yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0004887, HP:0000822

HPOsFreeText: GAA = 5.7%, smoker, BMI = 22.3, basilar artery fenestration, nucleo-capsular and temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 24yr disease duration, variants in cis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1551+1G>C

ClinVar: 554983, https://www.ncbi.nlm.nih.gov/clinvar/variation/554983/

gnomAD: n/a

Patient3: 53yo

CasePresentingHPOs: HP:0002870

HPOsFreeText: hyperCKemia, GAA = 16%, BMI = 27.7, left vertebral artery dominant, temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 24yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient5:

CasePresentingHPOs:

HPOsFreeText: Juvenile onset Pompe

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 0.000007972, https://gnomad.broadinstitute.org/variant/17-78082197-T-C

Patient 4: Male, 37yo at diagnosis, 41yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 2.1 (3-20), mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: NIV not used

CaseAddInfo: 10yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1437G>A (p.Lys479=)

ClinVar: 188044, https://www.ncbi.nlm.nih.gov/clinvar/variation/188044/

gnomAD: n/a

Patient7: Female, 49yo at diagnosis, 50yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.78 (3-20)

CaseNotHPOs:

NotHPOsFreeText: NIV and mobility aid not required

CaseAddInfo: 25yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C

Patient17: Male, 34yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:800, enzyme (μmol/g/h) = 0.75 (3-20), NIV required only after ERT began

CaseNotHPOs:

NotHPOsFreeText: mobility aid not required

CaseAddInfo: 17yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_001079803.2(GAA):c.896T>C (p.Leu299Pro)

ClinVar: 180144, https://www.ncbi.nlm.nih.gov/clinvar/variation/180144/

gnomAD: n/a

Case32

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.1933G>A (p.Asp645Asn)

ClinVar: 188728 https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/

gnomAD: African 6.599e-5, Overall 8.250e-6 http://gnomad.broadinstitute.org/variant/17-78086719-G-A

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant, 1 more patient has the same genotype

Case4

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.148_859-11del (p.Glu50Hisfs*37; exons2–4deletion)

CAID: CA658795223 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.148_859-11del

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.685_686insCGGC (p.Arg229fsProfs*102)

CAID: CA658795233 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.685_686insCGGC

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case64

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1655T>C (p.Leu552Pro)

ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case60

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1445C>G (p.Pro482Arg)

CAID: CA401366794 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1445C%3EG

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 1 person more with the same genotype

Case21

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.1129G>C (p.Gly377Arg)

ClinVar: 497033 https://www.ncbi.nlm.nih.gov/clinvar/variation/497033/

gnomAD: European (Non-Finnish) 2.356e-5, Overall 1.072e-5 http://gnomad.broadinstitute.org/variant/17-78082341-G-C

CaseAddInfo: Infantile Onset Pompe Disease

Patient2: Female, 34 years report, Iranian, Iran

CasePresentingHPOs: HP:0002098, HP:0003236, HP:0002910 (Respiratory distress, Increased serum CK, Increased transaminases)

HPOsFreeText: GAA measurement from dried blood specimen at pH 3.8 was 0.13 nmol/spot * 21 h (ref 0.9-7.2) with acarbose and 0.65 nmol/spot * 21 h (ref 1.5-10) without acarbose and 3.84 nmol/spot * 21 h at pH 7.0 (ref 1.8-17.1), AST levels at 165 (ref 0-45), ALT levels at 261 (ref 5-40), CPK levels at 1212 (ref 25-200), FEV1 at 0.83, FEV1/FVC at 90.25

CaseAddInfo: Sibling of P1

Case9: Female, 34 years report

HPOsFreeText: 6 years of ERT completed, 6 Minute Walking Test at 452 meters, Forced Vital Capacity at 76%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.1655T>C (p.Leu552Pro)

ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C

Variant2: NM_000152.4:c.1688A>T (p.Gln563Leu)

CAID: CA401368995 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1688A%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case19: Male, 57 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 273 meters, Forced Vital Capacity at 77%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1819_1836del (p.Gly607_His612del )

CAID: CA658795266 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1819_1836del

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Patient2: Female, 0.5mo at ERT start, 9.4yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 20mg/kg/2wk

CaseNotHPOs:

NotHPOsFreeText: no infusion associated reactions

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481 + 102_2646 + 31del)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Patient18: Male, 49yo

CasePresentingHPOs:

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 13yr disease duration, ERT lasted 84mo

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.794delG

CAID: CA658795237, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.794delG

gnomAD: n/a

Patient10: Female, 75yo

CasePresentingHPOs: HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 40yr disease duration, ERT lasted 103mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NC_000017.11:g.(?80118193)(80118357_?)del (del exon 18)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Patient5: Female

CasePresentingHPOs: HP:0004887, HP:0002194, HP:0001522

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis and ERT at 4mo, ERT lasted for 1mo, ventilation required at 3mo, died at 5mo, variants in trans

CasePMIDs: 21763167, 11738358

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/17-78086424-C-T

Patient13: Female

CasePresentingHPOs:

HPOsFreeText: ERT dosage = 20mg/kg/2w, HCM reversal, CRIM positive, able to run and climb stairs, can speak well

CaseNotHPOs: HP:0004887, HP:0009046

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 111mo, currently 10yo

CasePMIDs: 14695532, 14972326

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

Patient18: Male

CasePresentingHPOs: HP:0004887, HP:0003819

HPOsFreeText: ERT dosage = 20mg/kg/2w, able to hold objects, CRIM negative

CaseNotHPOs:

NotHPOsFreeText: No HCM reversal

CaseAddInfo: Symptom onset at 6mo, diagnosis and ERT at 12mo, ERT lasted for 9mo, required ventilation at 34mo, died at 42mo

CasePMIDs: 22252923, 27629047

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1657C>T

CAID: CA401368835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1657C%3ET

gnomAD: n/a

Case# Patient 1, male

CasePresentingHPOs: HP:0003236

CaseAddInfo: 14yo at onset, 16 at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro

ClinVar: 279811; https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 1.663e-05; http://exac.broadinstitute.org/variant/17-78085800-T-C

Patient5: Male, Hispanic, 14yo

CasePresentingHPOs:

HPOsFreeText: IOPD, rhGAA IgG antibody titer = 200, CRIM positive

CaseNotHPOs:

NotHPOsFreeText: no infusion associated reactions

CaseAddInfo: homozygous, 6.8mo at diagnosis, 7.3mo at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 0.000003998, https://gnomad.broadinstitute.org/variant/17-78090874-A-C

Patient3: Male, Caucasian, 11yo

CasePresentingHPOs:

HPOsFreeText: IOPD, negative rhGAA IgG antibody titer, CRIM positive

CaseNotHPOs:

NotHPOsFreeText: no infusion associated reactions

CaseAddInfo: diagnosed at birth, 15days old at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 0.00009959, https://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.5(GAA):c.1642G>T (p.Val548Phe)

ClinVar: 5973381, https://www.ncbi.nlm.nih.gov/clinvar/variation/597381/

gnomAD: n/a

Variant3: NM_000152.5(GAA):c.1880C>T (p.Ser627Phe)

ClinVar: 597382, https://www.ncbi.nlm.nih.gov/clinvar/variation/597382/

gnomAD: n/a

Case#: Patient 3

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None

CaseHPOFreeText: None

CaseNotHPOs: None

CaseNotHPOFreeText: None

CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine

Glucosidase activity: 0.0 nmol 5MU/hr/mL

Variant 1: NM_000152.5:c.596A>G

Variant 1 ClinVarID: 92486

Variant 1 CAid: CA145785

Variant 2: NM_000152.5:c.668G>A

Variant 2 ClinVarID: 92488

Variant 2 CAid: CA145791

ParentalGenotype: Not provided

Patient3: Male, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.2024A>G

CAID: CA401370120, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370120

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2132C>G (p.Thr711Arg)

ClinVar: 381006, https://www.ncbi.nlm.nih.gov/clinvar/variation/381006/

gnomAD: 0.0001488, http://exac.broadinstitute.org/variant/17-78087108-C-G

CaseA2: 31 years onset

CaseAddInfo: Late-Onset Pompe Disease, Sibling of A1

Case17: Male, 11 years onset, 15 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case#: Subject number 11, male, 23 years (diagnosis), 31 years (baseline visit), 24 years (ERT), 23 (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 12, female, 20 years (diagnosis), 46 years (baseline visit), 39 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 29, female, 40 years (diagnosis), 54 years (baseline visit), 48 (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

Case6: Male, 5 months report, birth onset, Algeria, African

CasePresentingHPOs: HP:0001635, HP:0001639, HP:0008872, HP:0002015, HP:0000961, HP:0003324, HP:0008936, HP:0000158, HP:0001315, HP:0001263, HP:0000467, HP:0002240, HP:0001640, HP:0002878, HP:0011950, HP:0001270, HP:0001290 (Heart failure, Hypertrophic cardiomyopathy, Feeding difficulties in infancy, Swallowing difficulties, Cyanosis, Generalized weakness, Axial hypotonia, Macroglossia, Decreased/absent deep tendon reflexes, Global developmental delay, Neck muscle weakness, Hepatomegaly, Cardiomegaly, Respiratory failure, Bronchiolitis, Motor delay, Generalized hypotonia)

HPOsFreeText: Intercostal and subcostal retraction, cardiothoracic ratio of about 0, 78%, CK, ALT, and AST rates were normal, GAA level is null

CaseAddInfo: Died at 11 months

Patient14: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.3:c.2376_2377insCA

CAID: CA913184735, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184735

Patient4: Female, southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.2185delC (p.Leu729Trpfs) **this is not the same protein transcript listed in paper (p.Thr729fsX8) but I could not find this in clinvar or allele registry)

ClinVar: 370552, https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/

gnomAD: n/a

Case#: P 18, Male, 1.4 months old when started ERT (Died at 36.4 months old)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0006532

(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Recurrent Pneumonia)

CaseHPOFreeText: Recurrent pneumonia was a complication during ERT

Best motor status was walking

CaseNotHPOs: N/A

CaseNotHPOFreeText: Did not required ventilation nor tube feeding

CasePreviousTesting: CRIM status was positive

Antibody titer was unknown

Variant: NM_000152.5(GAA):c.896T>C (p.Leu299Pro)

ClinVar: 180144

CAID: CA273686

gnomAD: N/A

ParentalGenotype: Both the paternal and maternal allele carried the variant NM_000152.5(GAA):c.896T>C (p.Leu299Pro)

PreviouslyPublished: N/A

Patient5: female

CasePresentingHPOs: HP:0001270

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:25.600, infusion associated reaction, heat normalization

CaseNotHPOs: HP:0004887, HP:0025156, HP:0001371

CaseAddInfo: homozygous variants in trans, symptom onset and diagnosis at 1yo, ERT at 2yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Patient13: female

CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365

HPOsFreeText: CRIM positive, tracheostomy, partial heart normalization

CaseNotHPOs: HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 6yo, diagnosis and ERT at 11yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)

ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

gnomAD: 5.884e-05, http://exac.broadinstitute.org/variant/17-78086713-G-A

Case14HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.1 umol/h/L, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C

CaseAddInfo:

Subject II-4: female

CasePresentingHPOs:

HPOsFreeText: normal GAA enzyme values

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: carrier status, clinically asymptomatic

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA genotyping

Variant: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034, https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Case#: 2/a, age 20, age 14 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 2, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 64.47 NaG/AaGIA, 92.28% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

ClinVar: 932904

Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: Subject number 6, male, 19 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: Family member with PD

CasePresentingHPOs:

CaseHPOFreeText: Asymptomatic

CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.37 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.281_282delCT (p.Pro94ArgfsTer?)

Variant 2 ClinVarID: 370458

Variant 2 CAid: CA16041881

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 7, male, 31 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.27 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

Variant 2 ClinVarID: 279811

Variant 2 CAid: CA8815429

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient1: Male, Birth onset

CasePresentingHPOs: HP:0001644, HP:0012420, HP:0002098, HP:0001640, HP:0002375, HP:0002789, HP:0001649, HP:0030148, HP:0001252, HP:0001712, HP:0025168, HP:0009128, HP:0002878 (Dilated cardiomyopathy, Meconium stained amniotic fluid, Respiratory difficulty, Cardiomegaly, Hypokinesia, Tachypnea, Tachycardia, Heart murmur, Muscle hypotonia, Left ventricular hypertrophy, Left ventricular diastolic dysfunction, Absent/underdeveloped muscles of extremities, Respiratory failure)

HPOsFreeText: Apgar scores were 2155, birth weight was 3,764 g, length was 50.5 cm, Mild diffuse pulmonary markings, Had a grade II ejection systolic murmur at the left upper sternal border with intermittent gallop, A cardiac catheterization with myocardial biopsy was performed on day of life 30 which revealed marked vacuolization of cardiac myocytes, Analysis of plasma GAA activity revealed a significant deficiency (4 pmoles/hr/spot, reference range 24–94), Moderately elevated urine glucose tetrasaccharide (Hex4) of 29.6 mmol/mol creatinine (reference range: <19 for age <6 months)

NotHPOsFreeText: The ECG showed sinus rhythm with a ventricular right axis deviation without pathognomonic changes of Pompe disease, Extremities were freely moveable, Newborn screening was normal

CaseAddInfo: Non‐consanguineous product of a term pregnancy born to a G3P2 mother, Pregnancy was complicated by limited prenatal care, cannabinoid, and amphetamine use, Family history was negative for neuromuscular diseases but significant for multiple sclerosis and seizure disorders

Patient 15 - IOPD - homozygous

Variant: NM_000152.4(GAA):c.925G>A (p.Gly309Arg)

ClinVar: 188797, https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: 0.00002860, http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Case#: Patient 6, gender unknown, age unknown, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0003756

(Cardiomyopathy, Skeletal myopathy)

CaseHPOFreeText:N/A

CaseNotHPOs: N.A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sequence analysis of the GAA gene was performed in a CLIA and CAP certified laboratory.

Cross Reactive Immune reaction was negative in peripheral blood mononuclear cells (PBMCs)

Cross Reactive Immune reaction was not available in Dried blood spots.

Variant: NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102

CAID: CA8815680

gnomAD: Highest population MAF= 0.00005441 (East asian)

ParentalGenotype: N/A

PreviouslyPublished:N/A

Patient10: Female, 1.5mo at diagnosis, 2mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, good response to ERT, Pompe muscle pathology score = 0.2, Glycogen = 3.1 Vv(PAS + /mf)%, larger empty vacuoles = 0 Vv (LEV/mf)%,

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1157_1158insA

CAID: CA658655614, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658655614

gnomAD: n/a

PatientF3P2: Female, 36 years diagnosis, European and Native American

CasePresentingHPOs: HP:0003236, HP:0012378, HP:0003547, HP:0009113, HP:0002910 (Increased serum CK, Fatigue, Shoulder weakness, Weak diaphragm, Increased transaminases)

HPOsFreeText: Decline in energy and strength reported with each of her four pregnancies most prominent after her youngest daughter's diagnosis of IOPD, Subsequent enzyme assay indicated deficient GAA activity via a dried blood spot (2.2 pmol/punch/hr, control >3.88 pmol/punch/hr), Pulmonary functioning tests (PFTs) showed a decrease in forced vital capacity (FVC) from 93% predicted seated to 72% predicted supine, Laboratory results demonstrated an elevated CK level of 490 U/L (control 30–220 U/L) and mild elevation of transaminases with AST of 83 U/L (control 15–41 U/L) and ALT of 60 U/L (control 14–54 U/L)

CaseAddInfo: Mother of proband F3P1, found to have minimally symptomatic LOPD

Case9: Female, 5 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421 (Epistaxis)

CaseHPOFreeText: Hematomas at the site of injury

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: HP:0000421

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.1230del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940214

gnomAD: N/A

Case8: Female, 3 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364 (Epistaxis, gingival bleeding, ecchymosis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.1073del

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940580

gnomAD: N/A

Case7: Male, 1.5 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0031364, HP:0000421 (Ecchymosis, epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.2315C>G (p.Pro772Arg)

LegacyVariant: (p.Pro741Arg)

ClinVar: N/A

CAiD: CA8602740

gnomAD: MAF in the South Asian population is 0.0002613 https://gnomad.broadinstitute.org/variant/17-42453709-G-C

Case6: Female, 7 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225 (Gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.1374C>G (p.Ile458Met)

LegacyVariant: (p.Ile427Met)

ClinVar: N/A

CAiD: CA8603157

gnomAD: MAF in the South Asian population is 0.003658 https://gnomad.broadinstitute.org/variant/17-42458266-G-C

Case5: Female, 3 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225

(Epistaxis, gingival bleeding)

CaseHPOFreeText: Severe epistaxis and mild gum bleeding

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.859G>C (p.Gly287Arg)

LegacyVariant: (p.Gly256Arg)

ClinVar: N/A

CAiD: CA399805008

gnomAD: N/A

Case4: Female, 18 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0000132

(Gingival bleeding, menorrhagia)

CaseHPOFreeText: Menorrhagia only during puberty

CaseNotHPOs: N/A

CaseNotHPOFreeText:N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.2264G>C (p.Arg755Pro)

LegacyVariant: (p.Arg724Pro)

ClinVar: N/A

CAiD: CA8602772

gnomAD: MAF in the European (non-Finnish) population is 0.00001060 https://gnomad.broadinstitute.org/variant/17-42454380-C-G

Case3: Male, 40 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0002239, HP:0002248

(Epistaxis, GI bleeding, hematemesis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.310+1G>A (IVS2(+1)G>A)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA8603502

gnomAD: MAF in the European (non-Finnish) population is 0.00001771 https://gnomad.broadinstitute.org/variant/17-42463377-C-T

Case2: Male, 3 years old, Indian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0030137 (Prolonged bleeding following circumcision)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: Diagnosis of GT was made on the basis of quantitive determination of receptor count by flow cytometric analysis of GPIIb-IIIa

PlateletAggregation: Diagnosis of GT was made on the basis of impaired platelet aggregation (platelet aggregation was tested against ristocetin, ADP, collagen, epinephrine and arachidonic acid)

CasePreviousTesting: Multiplex PCR by using GPIIb primers and CSGE analysis were performed

Gene: ITGA2B

Variant: NM_000419.3:c.1652G>A (p.Arg551Gln)

LegacyVariant: (p.Arg520Gln)

ClinVar: N/A

CAiD: CA8602986

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

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: (GTa) Female, 27 years old, Irish Caucasian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: No family history of bleeding

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978

(Bruising)

CaseHPOFreeText: Excessive bleeding after a normal delivery

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Reduced expression of GPIIb/IIIa

PlateletAggregation: Platelet aggregation to ADP, thrombin receptor activating peptide, thrombin and U46619 was less than 10% and ristocetin induced agglutination was normal

CasePreviousTesting: Total RNA isolated from the proband's platelets was used as a template for RT PCR. Seven primer pairs were used to amplify overlapping regions of the entire GPIIIa coding sequence using cDNA template

Gene: ITGB3

Variant: NM_000212.2:c.655G>A (p.Val219Met)

LegacyVariant: (p.Val193Met)

ClinVar: N/A

CAiD: CA8623016

gnomAD: MAF in the South Asian population is 0.00003266 http://gnomad.broadinstitute.org/variant/17-45363666-G-A

Case5: Patient M5, Female, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

ParentalGenotype: Unaffected parents see pedigree Fig 2

CasePresentingHPOs: N/A

CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Case10: Patient M10, Male, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

ParentalGenotype: Unaffected parents see pedigree Fig 2

CasePresentingHPOs: N/A

CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Case1: Patient M1, Female, French Gypsy, age is not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: See Figure 2 for pedigree

ParentalGenotype: Unaffected parents see pedigree Fig 2

CasePresentingHPOs: N/A

CaseHPOFreeText: France, GT is particularly frequent in the Gypsy population, mainly represented by the Manouche tribe. Their clinical phenotype is the same as for classic type I disease, with a moderate and occasional severe bleeding syndrome

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry analysis has shown that these patients' surface expresses <5% of normal GPIIIa and GPIIb levels (we are not given an exact value for each proband)

PlateletAggregation: "Absent platelet aggregation" this is all the information we are given for platelet aggregation

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Case1: 39 years old, Female, Jewish Iraqi

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients demonstrated lack of αIIbβ3 surface expression." No specifics are given on the percentage, but test was performed

PlateletAggregation: Presented with mucocutaneous bleeding, absence of platelet aggregation in response to all physiological agonists in contrast to normal aggregation with ristocetin

CasePreviousTesting: "Molecular analysis disclosed that patient 2 was homozygous for an out of frame mutation (c.2031–2041 del, exon 13) in ITGB3, and patient 4 was compound heterozygote for the same deletion and a large deletion of 11.2Kb del"

Gene: ITGB3

Variant: NM_000212.2:c.2051_2061del (c.2051_2061del)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA915940226

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