Patient7: Male, 59yo

CasePresentingHPOs: HP:0000822, HP:0000819, HP:0003077, HP:0001513

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 14yr disease duration, ERT lasted for 135mo

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.307T>G (p.Cys103Gly)

ClinVar: 92483, https://www.ncbi.nlm.nih.gov/clinvar/variation/92483/

gnomAD: n/a

Patient1: Female 26yo

CasePresentingHPOs: HP:0003077

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5year follow-up MRI, 15yr disease duration, ERT lasted for 67mo

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: IVS9 G > C no ClinVar or CAID

Patient12: Female, 66yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 7yr disease duration, ERT lasted 33mo

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

Patient17: Male, 81yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 6yr disease duration, ERT lasted 37mo

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.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

Patient4: Male, 50yo

CasePresentingHPOs: HP:0003077, HP:0005978

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 18yr disease duration, ERT lasted 130mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as grou

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.1495T>A

CAID: CA198789, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA198789

gnomAD: n/a

Patient3: Male, 50yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr follow-up MRI, 40yr disease duration, ERT lasted for 116mo

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: c.2136-7delGT no ClinVar, no CAID

Patient9: Male, 64yo

CasePresentingHPOs: HP:0000822, HP:0000819, HP:0001513

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 11yr disease duration, ERT lasted 14mo

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.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

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

Case21HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.8 U/g, GAA activity at 8.9% 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

No information given to identify where the variant is

Variant2: NM_000152.4: IVS15+2T>A

ClinVar:

gnomAD:

CaseAddInfo:

Case12HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 4 nmol/punch/hr, GAA activity at 15% 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.546+1G>T

CAID: CA401361913 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo:

Case8HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 8 pmol/punch/hr, 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.2242dupG (p.Glu748Glyfs)

ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/

gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG

CaseAddInfo:

Case2HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 6 pmol/punch/hr, GAA activity at 25% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

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:

CaseLOPD-11: 8.3 years 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

Variant2: NP_000143.2:p.Q743∗ 

ClinVar: N/A

gnomAD: N/A

CaseAddInfo: Late Onset Pompe Disease

CaseLOPD-19: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.8%

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

Variant2: NM_000152.4:c.1115A>T (p.His372Leu)

ClinVar: 370483 https://www.ncbi.nlm.nih.gov/clinvar/variation/370483/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

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

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

Case16: Female, 61 years report

HPOsFreeText: 7 years of ERT completed, 6 Minute Walking Test at 392 meters, Forced Vital Capacity at 52%

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.693-1G>C

CAID: CA401362948 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.693-1G%3EC

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case32: Female, 45 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 533 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.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

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

Patient21: Male, 56yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.57 (2-10), NIV and mobility aid required before and after ERT, developed wheelchair dependence after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 35yr 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.1128_1129delGGinsC (p.Trp376Cysfs)

ClinVar: 189041, https://www.ncbi.nlm.nih.gov/clinvar/variation/189041/

gnomAD: n/a

Patient22: Female, 40yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:12,800, enzyme = 2.77 pmol/punch/h (7.3–39), NIV and mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 18yr disease duration, patient discontinued ERT, 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.258dupC (p.Asn87Glnfs)

ClinVar: 282842, https://www.ncbi.nlm.nih.gov/clinvar/variation/282842/

gnomAD: 2.653e-05, http://exac.broadinstitute.org/variant/17-78078636-T-TC

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

Case#: Subject number 8, female, 32 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 0.3 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.925G>A (p.Gly309Arg)

Variant 2 ClinVarID: 188797

Variant 2 CAid: CA273972

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 13, female, 57 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress)

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 0.37 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.2237G>C (p.Trp746Ser)

Variant 2 ClinVarID: 188484

Variant 2 CAid: CA198797

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 2, female, 7 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: Family member with PD

CasePresentingHPOs:

CaseHPOFreeText: Asymptomatic

CaseNotHPOs: 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), HP:0001638 (cardiomyopathy)

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 0.12 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.1396_1397insG (p.Val466GlyfsTer?)

Variant 2 ClinVarID: ?

Variant 2 CAid: CA627699396

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 9, female, 44 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress)

CaseHPOFreeText:

CaseNotHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), 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 0.34 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.2819C>A (p.Ser940Ter)

Variant 2 ClinVarID: ?

Variant 2 CAid: CA401327757

Zygosity: Compound heterozygous

ParentalGenotype: 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

Case5: Male, 65 years onset, 72 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 72, GAA Activity at ~6 pmol/min/mg before ERT and ~10.5 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.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

CaseAddInfo: Late Onset Pompe Disease

Case15: Female, 39 years onset, 40 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 41, GAA Activity at ~6.5 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.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case14: Female, 15 years onset, 16 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 16, GAA Activity at ~8 pmol/min/mg before ERT and ~12 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.1927G>A (p.Gly643Arg)

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

gnomAD: European (Non-Finnish) 3.667e-5, Overall 2.479e-5 http://gnomad.broadinstitute.org/variant/17-78086713-G-A

CaseAddInfo: Late Onset Pompe Disease

CaseP3-GAA: male, ethnicity = European, country origin = Italy

CasePresentingHPOs:

HPOsFreeText: enzyme activity = 1.97

CaseNotHPOs: HP:0010899, HP:0010916, HP:0003236

CaseAddInfo: known psuedodeficiency alleles (c.1726G>A and c.2065G>A)

CasePreviousTesting: initial and confirmatory DBS, biochemical tests

CaseGenotypingMethod: mutation analyses

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

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

gnomAD: n/a

CaseP1-GAA: Male, ethnicity = North African, country origin = Morocco

CasePresentingHPOs: HP:0010899, HP:0010916, HP:0003236

HPOsFreeText: enzyme activity = 0.61, CPK = 448 U/L, ALT = 48 U/L, AST = 98 U/L, CRIM positive

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: heterozygote, variants in trans. Patient underwent ERT.

CasePreviousTesting: initial and confirmatory DBS, biochemical tests, echocardiography

CaseGenotypingMethod: mutation analyses

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

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

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

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

gnomAD: n/a

Case#: Patient 11, male

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 24yo at onset, 47yo 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: NC_000017.11:g.(?80118193)(80118357_?)del

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

gnomAD: n/a

Case#: Patient 14, male

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 50yo at onset, 66yo 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: c.2219-20dTG, p.Val740GfsX55 No ClinVar or CAID

Case#: Patient 6, female

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 55yo at onset, 59yo 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.1561G>A (p.Glu521Lys)

ClinVar: 4022, https://www.ncbi.nlm.nih.gov/clinvar/variation/4022/

gnomAD: 8.262e-06, http://exac.broadinstitute.org/variant/17-78084749-G-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

Case13: Male, 9 years onset, 19 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

CaseB: 40 years onset

CaseAddInfo: Late-Onset Pompe Disease

Case17: Male, 13 yr onset, 14 yr diagnosis, 14.3 yr report

HPOsFreeText: FVC z-score sitting -1.68 (81% pred), FVC z-score supine -1.77 (80% pred), 95% MRC Scale, 2935 CK U/l, 6.2 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case10: Male, 2.5 yr onset, 3 yr diagnosis, 13 yr report

CasePresentingHPOs: HP:0001371 (Contractures)

HPOsFreeText: FVC z-score sitting -3.01 (66% pred), FVC z-score supine -4.09 (54% pred), 84% MRC Scale, 1960 CK U/l, 8.6 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case2: Female, Birth diagnosis, 0.8 yr onset

HPOsFreeText: 258 CK U/l, Deficient GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, no respiratory support

Case56

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.1796C>A (p.Ser599Tyr)

ClinVar: 551558 https://www.ncbi.nlm.nih.gov/clinvar/variation/551558/

gnomAD: European (Non-Finnish) 2.683e-5, Overall 1.207e-5 http://gnomad.broadinstitute.org/variant/17-78086418-C-A

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: Juvenile Late Onset Pompe Disease

Case85

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.784G>A (p.Glu262Lys)

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

gnomAD: East Asian 5.016e-5, Overall 1.417e-5 http://gnomad.broadinstitute.org/variant/17-78081447-G-A

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, 2 other patients have the same genotype

Case77

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.-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

Case58

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.1143delC (p.Ala382Leufs*10)

CAID: 370263 https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/

gnomAD: European (Non-Finnish) 8.946e-6, Overall 4.031e-6 http://gnomad.broadinstitute.org/variant/17-78082353-AC-A

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

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

Case18: Female, Unknown years onset, Unknown years diagnosis, 25 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case11: Male, 24 years onset, 58 years diagnosis, 62 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Scapula alata)

CaseAddInfo: Late-Onset Pompe Disease

Patient16: 16yo

CasePresentingHPOs: HP:0003325, HP:0020038

HPOsFreeText: GAA = 4.5%, BMI = 21.4, fetal origin of right posterior cerebral artery, normal CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 6yr 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_000152.3:c.2530_2541del

CAID: CA658795292, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795292

gnomAD: n/a

Patient17: 65yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002870, HP:0020038, HP:0002637

HPOsFreeText: GAA = 6.8%, smoker, BMI = 27.1, right ventricular trigone retraction due to ischemia

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 22yr disease duration, variants in cis

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.1561G>A (p.Glu521Lys)

ClinVar: 4022, https://www.ncbi.nlm.nih.gov/clinvar/variation/4022/

gnomAD: 8.262e-06, http://exac.broadinstitute.org/variant/17-78084749-G-A

Patient20: 60yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0000822, HP:0002870, HP:0020038

HPOsFreeText: GAA = 11%, BMI = 23.2, subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr disease duration, variants in cis

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.1561G>A (p.Glu521Lys)

ClinVar: 4022, https://www.ncbi.nlm.nih.gov/clinvar/variation/4022/

gnomAD: 8.262e-06, http://exac.broadinstitute.org/variant/17-78084749-G-A

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

Case#: Subject number 17, female, 33 years (report), 14 years (onset), 24 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000360 (tinnitus)

CaseHPOFreeText: ambulatory

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

CaseNotHPOFreeText: no infusion reaction, 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.2104C>T

Variant 2 ClinVarID: 189040

Variant 2 CAid: CA274304

Zygosity: Compound heterozygous

ParentalGenotype: N/A

Case#: Subject number 3, male, 56 years (report), 30s years (onset), 48 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A ** CasePresentingHPOs**: HP:0000365 (hearing loss), HP:0000360 (tinnitus)

CaseHPOFreeText: ambulatory

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

CaseNotHPOFreeText: No infusion reaction, 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.2431delC (p.Leu811TrpfsTer?)

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA628018649

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 16, male, 64 years (report), 56 years (onset), 60 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText: on BiPAP, ambulatory, assistive device (cane)

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.307T>G

Variant 2 ClinVarID: 92483

Variant 2 CAid: CA220404

Zygosity: Compound heterozygous

ParentalGenotype: N/A

Case#: Subject number 8, female, 49 years (report), 20s years (onset), 42 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000821 (hypothyroidism)

CaseHPOFreeText: ambulatory, assistive device (quad cane, wheelchair)

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

CaseNotHPOFreeText: No infusion reaction, 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.1437+2T>C

Variant 2 ClinVarID: 849313

Variant 2 CAid: CA401366685

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 5, male, 59 years (report), 10 years (onset), 33 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000365 (hearing loss), HP:0000360 (tinnitus), HP:0000939 (osteoporosis)

CaseHPOFreeText: Tracheostomy, assistive device (wheelchair)

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

CaseNotHPOFreeText: No infusion reaction, no ambulatory, 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.925G>A (p.Gly309Arg)

Variant 2 ClinVarID: 188797

Variant 2 CAid: CA273972

Zygosity: Compound heterozygous

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

Patient5: female, 53yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 21.1 / 21.1 / 22.5, WGMS = 3 / 3 / 3

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

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

CaseVI,3: Adult onset, 64 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003236 (Proximal muscle weakness, Abnormal respiration, Increased serum CK)

HPOsFreeText: GAA activity from dried blood spot: 0.16%, Forced Vital Capacity Seated: 1550 (48%), Plasma CK 2.5-5x Normal

CaseAddInfo: Late-Onset Pompe Disease

Case#: Patient 1, woman, 58 years old, ethnicity unknown

DiseaseAssertion:Pompe disease

Was also misdiagnosed with adult-onset spinal muscular atrophy (SMA)

FamilyInfo: No family history of muscle disease

CasePresentingHPOs: HP:0003701, HP:0100284

(Proximal muscle weakness, EMG myotonic discharges)

CaseHPOFreeText: Denervation atrophy from a muscle biopsy

Weakness of hip flexion 2–3/5, hip abduction 2/5, and hip adduction 2/5

Myotonic discharges were in the lumbar paraspinals, vastus medialis, and tensor fasciae latae muscles.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA enzyme activity assay was 1 pmol/punch/h (normal range 10–49 pmol/punch/h)

Her creatine kinase (CK) level at presentation had been elevated as high as 429 U/L (normal range 45–145)

Found with two mutations in the GAA gene

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

ClinVar: 4027

CAID: CA116606

gnomAD: Highest population MAF= 0.005541 (Ashkenazi Jewish)

Variant: NM_000152.5(GAA):c.525del (p.Glu176fs) Double check this variant

ClinVar: 4033

CAID: CA220406

gnomAD: N/A

ParentalGenotype:N/A

Previously Published: N/A

Subject II-6: female, 56yo

CasePresentingHPOs: HP:0000822, HP:0003701, HP:0001611, HP:0003691, HP:0003700, HP:0009023, HP:0003307, HP:0002515, HP:0040081, HP:0003458

HPOsFreeText: altered DBS, treated with beta-blockers, occasional cramping of lower limbs, muscle atrophy of temporal, deltoids, and thigh muscle extensors, muscle strength was 5/5 proximal and distal for upper limbs and distal for lower limbs, and 4/5 on hip extension, diminished biceps, triceps, patellar, and ankle jerk reflexes. Intact pain, temperature, vibration, proprioception, and coordination. CK = 86 IU/L, AST = 33 IU/L, reduced GAA activity, reduced duration and amplitude of motor unit action potentials (mainly on thigh extensors), normal muscle biopsy

CaseNotHPOs: HP:0001291, HP:0002015, HP:0001618, HP:0003391, HP:0003487

NotHPOsFreeText: no Hoffmann sign, paraspinal complex repetitive discharges

CaseAddInfo: This patient's 5 daughters had DBS and GAA sequencing evaluations, only 2 (III-9 and III-10) had altered DBS and carried GAA variants

CasePMIDs:

CasePreviousTesting: DBS, EMG, muscle biopsy from thigh extensors

CaseGenotypingMethod: GAA genotyping

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.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

Case7: Male, Danish, 20 years report, 1 year onset

HPOsFreeText: MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 5.6/5.3 (L), Has started ERT

CaseNotHPOs: HP:0008956 (Thigh muscle atrophy)

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

Variant1: NM_000152.4:c.2228A>G (p.Gln743Arg)

CAID: CA401324753 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2228A%3EG

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.2237G>C (p.Trp746Ser)

ClinVar: 188484 https://www.ncbi.nlm.nih.gov/clinvar/variation/188484/

gnomAD: African 3.210e-4, Overall 7.089e-5 http://gnomad.broadinstitute.org/variant/17-78090814-G-C

Variant3: 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: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

Patient2: female, 29 yo, Caucasian

CasePresentingHPOs: HP:0003724, HP:0008988, HP:0003691, HP:0003391, HP:0003551, HP:0040081, HP:0002910, HP:0003557, HP:0100295, HP:0100295, HP:0009051, HP:0004356, HP:0002111

HPOsFreeText: paravertebral muscle atrophy, atrophies with paresis grade of 3-4 MRC, cannot stand from squatting position, impaired overhead work, CK = 1390 U/l, AST = 65 U/l, ALAT = 72 U/L, symmetrical atrophy of thigh muscle, fatty deposits in m. adductor magnus, flause signal elevation in the mm. semimembranosus and mm. biceps femoris bilateral, reticulation in the proximal vastus intermedius and vastus lateralis, vacuolated muscle fibres, PAS-positive glycogen storage with enhanced lysosomal activity in the PAS staining, increased lysosomal activity, GAA activity = 0.22nmol/spot x 21hrs

CaseNotHPOs: HP:0001639

CaseAddInfo:

CasePreviousTesting: MRI of thigh muscle, muscle biopsy of mm. vastus lateralis, hematoxylin and eosin stain, Peri acid-Schiff reaction, Acid phosphatase staining, transthoracic echocardiogram, respiratory function test

CaseGenotypingMethod: Sanger Sequencing

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

PatientF1P1: Female, 30 years onset, 40 years diagnosis, Caucasian

CasePresentingHPOs: HP:0007340, HP:0002172 (Leg weakness, Postural instability)

HPOsFreeText: History of hyperCKemia greater than 1,000 U/L (control 30–220 U/L), Showed deficient muscle acid GAA activity (0.05 µmol/min/g, control >0.42 µmol/min/g)

CaseAddInfo: First cousin twice removed of F1P3, Proband

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

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

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 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

Family 9 - Patient 9

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0010628, HP:0003306, HP:0002111, HP:0040081

HPOsFreeText: muscle pathology with slight vacuolar myopathy with mild glycogen excess

FamilyNotHPOs: HP:0002015, HP:0003691, HP:0002650

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: onset at 28yo, diagnosed at 35yo, MRC sum score = 81

FamilyPreviousTesting: Respiratory Evaluation: FVC = 71%, CK = 748 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 3.5 μmol/L/h

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

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.1799G>A (p.Arg600His)

ClinVar: 370130, https://www.ncbi.nlm.nih.gov/clinvar/variation/370130/

gnomAD: 8.675e-06, http://exac.broadinstitute.org/variant/17-78086421-G-A

Case3: Male, 27 years report, 20 years diagnosis, Germany

CasePresentingHPOs: HP:0002878 (Respiratory failure)

HPOsFreeText: 6-min walk test at 201 (m)

CaseNotHPOs:

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 7 years on ERT

Case3: Male, 27 years report, 20 years diagnosis, Germany

CasePresentingHPOs: HP:0002878 (Respiratory failure)

HPOsFreeText: 6-min walk test at 201 (m)

CaseNotHPOs:

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 7 years on ERT

Case#: Subject number 2, 37 years

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0008994 (proximal muscle weakness in lower limbs), HP:0003325 (limb-girdle muscle weakness), HP:0003701 (proximal muscle weakness), HP:0003691 (scapular winging), HP:0002355 (difficulty walking).

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Serum creatin kinase was 7.7 μkat/l

glucosidase activity: Whole uncoagulated blood samples used for leukocyte and DNA isolations.

GAA activity (w/o acarbose) 35 nmol.h.mg–1 (control 37±14).

8 nmol.h.mg–1 (with acarbose) (control 16±6).

Ratio of with/w/o acarbose is 0.24 (control 0.42±0.08).

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.1456G>C

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA401366835

Zygosity: compund heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 1, 18 years

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003325 (limb-girdle muscle weakness), HP:0008994 (proximal muscle weakness in lower limbs), HP:0008968 (muscle hypertrophy of the lower extremities), HP:0007340 (lower limb muscle weakness), HP:0003797 (limb-girdle muscle atrophy), HP:0002515 (waddling gait), HP:0003691 (scapular winging).

CaseHPOFreeText: Positive Trendelenburg sign

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Serum creatin kinase was 19. 9 μkat/l

glucosidase activity: Whole uncoagulated blood samples used for leukocyte and DNA isolations.

GAA activity (w/o acarbose) 29 nmol.h.mg–1 (control 37±14).

3 nmol.h.mg–1 (with acarbose) (control 16±6).

Ratio of with/w/o acarbose is 0.10 (control 0.42±0.08).

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