Case3: Male, 1 year report

CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)

HPOsFreeText: Nonspecific hyperCKemia, 847 CK (U/L), 0 GAA activity (µmol/L/h)

CaseNotHPOs: HP:0001627, HP:0002093 (Abnormality of the heart, Respiratory insufficiency)

Case2: Male, 2 years report

CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)

HPOsFreeText: Nonspecific hyperCKemia, 1710 CK (U/L), 0.1 GAA activity (µmol/L/h)

CaseNotHPOs: HP:0003457, HP:0001627, HP:0002093 (EMG abnormality, Abnormality of the heart, Respiratory insufficiency)

Case20: Female, 3 years onset, 4 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case#: Subject number 1, male, 22 years (report), 9 years (onset), 11 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002650, HP:0001638 (Scoliosis, cardiomyopathy)

CaseHPOFreeText: on BiPap, ambulatory

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

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.1655T>C (p.Leu552Pro)

Variant 1 ClinVarID:279811

Variant 1 CAid:CA8815429

Variant 1 gnomAD MAF: 0.00007053; 8/113426 (European non-Finnish)[https://gnomad.broadinstitute.org/variant/17-78085800-T-C?dataset=gnomad_r2_1]

Variant 2: NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)

Variant 2 ClinVarID:265160

Variant 2 CAid:CA9301331

Variant 2 gnomAD MAF: 0.0005673; 73/128684 (European non-Finnish)[https://gnomad.broadinstitute.org/variant/17-78090815-G-C?dataset=gnomad_r2_1]

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case46

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.525delT (p.Glu176Argfs*45)

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

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: 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

CaseAddInfo: Infantile Onset Pompe Disease

Case53

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.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

CaseAddInfo: Juvenile Late 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

Patient6: Female, 19mo at diagnosis, 22.5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 3.1, Glycogen = 38.5 Vv(PAS + /mf)%, larger empty vacuoles = 25.9 Vv (LEV/mf)%, Autophagic vacuoles = 0,13%/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

Variant2: NM_000152.3:c.524_525del

CAID: CA913184732, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184732

gnomAD: n/a

Patient6: Female, 53yo

CasePresentingHPOs: HP:0000822, HP:0003077, HP:0001513,

HPOsFreeText: LOPD, smoker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 17yr disease duration, ERT lasted for 99mo

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

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

gnomAD: n/a

Case#: case 1, male, 3 months old at diagnosis, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0001252 (cardiomyopathy, muscular hypotonia)

CaseHPOFreeText: (Associated with Pompe Disease): Interventricular septum hypertrophy, increased serum CK, increased serum tryptase

CaseHPOFreeText: (Infussion associated reactions) Urticarial rash, unresponsive to antihistamines and corticosteroids

CaseNotHPOs:

CaseNotHPOFreeText: Infusion associated reactions are not associated with an IgE mediated mechanism.

CasePreviousTesting:

GAA activity on fibroblast is 0.8 nmol/mg prot/h with a reference range of 64.4 ± 22.9 nmol/mg prot/h

GAA activity on lymphocytes is 2.2 nmol 4 Mu/mg prot/h with a reference range of 21.4 ± 6.2 nmol 4 Mu/mg prot/h

Variants:<br /> Variant 1: NM_000152.5(GAA):c.236_246del (p.Pro79fs)

ClinVar: 371302

CAID: 16041880

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

ClinVar:279811

CAID: 8815429

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case5: Female, French, 30 years report, 27 years onset

HPOsFreeText: 6-min walk test achieved 488 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 2.4/2.2 (L), Has started ERT

CaseNotHPOs: HP:0008956 (Thigh muscle atrophy)

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

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 https://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

Case6: Male, 25 years onset, 56 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 57, GAA Activity at ~10.5 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

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 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: 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

CaseAddInfo: Late Onset Pompe Disease

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

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

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 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