Patient7: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1432G>A (p.Gly478Arg)

ClinVar: 551295, https://www.ncbi.nlm.nih.gov/clinvar/variation/551295/

gnomAD: 8.525e-06, http://exac.broadinstitute.org/variant/17-78083849-G-A

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

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

gnomAD: n/a

Patient15: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

Variant2: NM_000152.3:c.1298A>C

CAID: CA401365381, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401365381

gnomAD: n/a

Patient2: Female, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

Variant2: NM_000152.3:c.859-2A>T

CAID: CA401363789, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401363789

gnomAD: n/a

GroupPresentingHPOs: HP:0001324, HP:0001270, HP:0002205, HP:0002098, HP:0001635, HP:0001640, HP:0011968

HPOsFreeText: IOPD, reduced GAA activity, paucity of movements

GroupNotHPOs:

NumberMales: 14

NumberFemales: 11

CountryOrigin: mainland China; 12 patients from southern China, 13 from northern China

Ethnicity: Chinese

Race: Chinese

AgeRange: median age at symptom onset = 3.4mo, median age at diagnosis = 4.9mo

TotalNumber: 25

FamilyInfo: Parents of those individuals with mutations were sequenced

NoFamily: n/a

GroupAddInfo: all patients diagnosed with IOPD between 2013 and 2016 at Shanghai Children's Medical Center. Of the 24 untreated patients, non survived beyond 1.5yrs, only surviving (Patient 25) was 7mo at last follow-up.

GroupPreviousTesting: IOPD diagnosed via reduced GAA enzyme activity in leukocytes or DBS (PMID: 16702880)

GroupGenotypingMethod: DNA isolated from blood samples, coding exons (2-20) and intron/exon boundaries of GAA gene amplified via PCR (primers: PMID: 10338092), resulting DNA was sequenced with ABI3730XL sequencer then was analyzed with Mutation Survey or DNA Variant Analysis software, novel mutations were screened in 60 normal individuals (120 alleles) via direct sequencing and no novel variants were found among these suggesting those found in study patients are uncommon polymorphisms.

fragments containing a mutation in the patients were amplified and sequenced for the corresponding parents

Phylogenetic conservation of missense mutations analyzed with ClustalX program, and pathogenicity of novel variants predicited with MutationTaster, sorting intolerant from tolerant (SIFT), and PolyPhen-2

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

this was identified (by present study) as the most common variant in northern Chinese patients, heterozygous for 5 patients, homozygous for one patient

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

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

Patient9: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.796C>T (p.Pro266Ser)

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

gnomAD: n/a

Variant2: NM_000152.3:c.1602_1605delinsAGG

CAID: CA913184733, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184733

gnomAD: n/a

Patient1: Female, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

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

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

Patient21: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

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

gnomAD: n/a

Variant2: NM_000152.3:c.1844G>T

CAID: CA401369601, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369601

gnomAD: n/a

Patient24: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1151 + 2T > G no ClinVar or CAID, intronic position inside exon

Variant2: NM_000152.3:c.1562A>T

CAID: CA401367205, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401367205

gnomAD: 0.000003980, http://gnomad.broadinstitute.org/variant/17-78084750-A-T

Case2

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.1195-19_2190-17del (p.Asp399fs*6)

CAID: CA658795244 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1195-19_2190-17del

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

Case22

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.1710C>G (p.Asn570Lys)

ClinVar: 555153 https://www.ncbi.nlm.nih.gov/clinvar/variation/555153/

gnomAD: African 1.149e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78085855-C-G

CaseAddInfo: Infantile Onset Pompe Disease

Case36

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.437delT (p.Met146Argfs*7)

ClinVar: 554096 https://www.ncbi.nlm.nih.gov/clinvar/variation/554096/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case88

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.836G>A (p.Trp279*)

CAID: CA401363637 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.836G%3EA

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

Case12

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.1654delC (p.Leu552Serfs*26)

CAID: CA658795262 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1654delC

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case65

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.1798C>T (p.Arg600Cys)

CAID: CA8815481 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1798C%3ET

gnomAD: South Asian 3.267e-5, Overall 4.025e-6 http://gnomad.broadinstitute.org/variant/17-78086420-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

Case51

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.-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: Infantile Onset Pompe Disease

Patient15: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

Variant2: NM_000152.3:c.1298A>C

CAID: CA401365381, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401365381

gnomAD: n/a

Patient20: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1320_1322del (p.Met440del)

ClinVar: 526518, https://www.ncbi.nlm.nih.gov/clinvar/variation/526518/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

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

gnomAD: 0.0002146, http://exac.broadinstitute.org/variant/17-78092070-C-T

Case#: Subject number 11(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 421 U/L (60-305 U/L is normal)

glucosidase activity: GAA activity (NBS) 0.63 in dried blood spots (>2.10 micromole/L/h is normal). 3.00 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.2560C>T

Variant 2 ClinVarID: 4034

Variant 2 CAid: CA340130

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 13(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 122 U/L (60-305 U/L is normal), AST: 78 U/L (20-64 U/L is normal), ALT: 42 U/L (12-42 U/L is normal), Hex4: 4.8 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 71.8 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 0.56 micromole/L/h and GAA activity #2 (NBS) 0.62 in dried blood spots (>2.10 micromole/L/h is normal). 3.80 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 5(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 333 U/L (28-300 U/L is normal), AST: 52 U/L (24-72 U/L is normal), ALT: 46 U/L (17-63 U/L is normal), Hex4: 4.4 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.82 micromole/L/h and GAA activity #2 (NBS) 0.94 in dried blood spots (>2.10 micromole/L/h is normal). 6.9 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 4(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 361 U/L (28-300 U/L is normal), AST: 66 U/L (24-72 U/L is normal), ALT: 52 U/L (17-63 U/L is normal), Hex4: 3.9 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.24 micromole/L/h and GAA activity #2 (NBS) 0.67 in dried blood spots (>2.10 micromole/L/h is normal). 2.4 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 27(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 108 U/L (60-305 U/L is normal), AST: 32 U/L (22-71 U/L is normal), ALT: 29 U/L (7-50 U/L is normal), Hex4: 3.3 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 35.7 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 (NBS) is 1.1 micromole/L/h and GAA activity #2 (NBS) 0.42 in dried blood spots (>2.10 micromole/L/h is normal). 2.40 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.1441T>C

Variant 1 ClinVarID: 189007

Variant 1 CAid: CA274247

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

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Variant 3: NM_000152.5(GAA):c.2065G>A

Variant 3 ClinVarID: 4030

Variant 3 CAid: CA116612

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 15(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 68 U/L (60-305 U/L is normal), AST: 49 U/L (20-64 U/L is normal), ALT: 27 U/L (12-42 U/L is normal), Hex4: 2.8 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.11 micromole/L/h and GAA activity #2 (NBS) 0.5 in dried blood spots (>2.10 micromole/L/h is normal). 1.60 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.2238G>C

Variant 1 ClinVarID: 265160

Variant 1 CAid: CA8815665

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

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Variant 3: NM_000152.5(GAA):c.2065G>A

Variant 3 ClinVarID: 4030

Variant 3 CAid: CA116612

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 24(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 197 U/L (60-305 U/L is normal)

glucosidase activity: GAA activity #2 (NBS) 0.43 in dried blood spots (>2.10 micromole/L/h is normal).

Variant 1: NM_000152.5(GAA):c.1856G>A

Variant 1 ClinVarID: 370146

Variant 1 CAid: CA8815500

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 21(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 155 U/L (60-305 U/L is normal), AST: 71 U/L (22-71 U/L is normal), ALT: 60 U/L (7-50 U/L is normal), Hex4 12.6 mmol/mol Creatine (≤20 is normal)

glucosidase activity: GAA activity #1 was 1.77 micromole/L/h and GAA activity #2 (NBS) 0.84 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 19(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 510 U/L (60-305 U/L is normal), AST: 158 U/L (22-71 U/L is normal), ALT: 39 U/L (7-50 U/L is normal), Hex4: 8.1 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP <10.0 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 1.07 micromole/L/h and GAA activity #2 (NBS) 0.38 in dried blood spots (>2.10 micromole/L/h is normal). 1.10 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.456_458insGA

Variant 1 ClinVarID: ?

Variant 1 CAid: ?

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

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 18(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 542 U/L (60-305 U/L is normal), AST: 152 U/L (22-71 U/L is normal), ALT: 55 U/L (7-50 U/L is normal), Hex4: 7.6 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 16.5 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 0.7 micromole/L/h and GAA activity #2 (NBS) 0.34 in dried blood spots (>2.10 micromole/L/h is normal). 1.40 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.2560C>T

Variant 2 ClinVarID: 4034

Variant 2 CAid: CA340130

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 9(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 145 U/L (60-305 U/L is normal), AST: 72 U/L (22-71 U/L is normal), ALT: 43 U/L (7-50 U/L is normal), Hex4: 5.3 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal), BNP 13.0 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 0.97 micromole/L/h and GAA activity #2 (NBS) 0.33 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.2238G>C

Variant 1 ClinVarID: 265160

Variant 1 CAid: CA8815665

Variant 2: NM_000152.5(GAA):c.2281delGinsAT

Variant 2 ClinVarID: 370993

Variant 2 CAid: CA16041905

Variant 3: NM_000152.5(GAA):c.2065G>A

Variant 3 ClinVarID: 4030

Variant 3 CAid: CA116612

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

CaseOPOPD-75: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.83 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.2815_2816delGT (p.Val939Leufs)

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

gnomAD: East Asian 1.631e-4, Overall 1.194e-5 http://gnomad.broadinstitute.org/variant/17-78093082-CTG-C

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

CaseLP2-11: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.46 umol/hr/L, Serum CK at 86 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.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

Variant4: 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: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 and Variants 3 and 4 are in cis

CaseOPOPD-70: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.47 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.2238G>T (p.Trp746Cys)

CAID: CA401324771 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2238G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CasePDC-9: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.98, MS/MS ennzyme activity at 0.83

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.2815_2816delGT (p.Val939Leufs)

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

gnomAD:East Asian 1.631e-4, Overall 1.194e-5 http://gnomad.broadinstitute.org/variant/17-78093082-CTG-C

CaseAddInfo: Patient is either a carrier or has a pseudodeficency allele

CaseOPTPD-6: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.50 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.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

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy, 70 other patients have the same genotype

CaseOPOPD-11: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.98 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.701C>T (p.Thr234Met)

ClinVar: CA8814994 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.701C%3ET

gnomAD: South Asian 3.266e-5, Overall 1.196e-5 http://gnomad.broadinstitute.org/variant/17-78081364-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

CaseLP-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.44, MS/MS ennzyme activity at 0.08

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.3:c.424_440del (p.Ser142Leufs*29)

CAID: CA658795228 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.424_440del17

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1958C>A (p.Thr653Asn)

CAID: CA8815557 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1958C%3EA

gnomAD: East Asian 2.548e-4, Overall 1.825e-5 http://gnomad.broadinstitute.org/variant/17-78086744-C-A

CaseAddInfo: Suspected Late Onset Pompe Disease

CaseIP2-2: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.09 umol/hr/L, Serum CK at 458 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.872T>C (p.Leu291Pro)

CAID: CA401363854 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.872T%3EC

gnomAD: Not in gnomAD

Variant2: 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

Variant3: 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 Variant 1 and 2 are in trans, also that Variant 3 is in cis with only one of them

CasePDC-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 1.15, MS/MS ennzyme activity at 1.2

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

CaseAddInfo: Patient is either a carrier or has a pseudodeficency allele, Second allele is wildtype

CaseLP-2: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.85, MS/MS ennzyme activity at 0.42

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.671G>A (p.Arg224Gln)

CAID: CA8814958 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.671G%3EA

gnomAD: African 8.060e-5, Overall 2.549e-5 http://gnomad.broadinstitute.org/variant/17-78079672-G-A

Variant2: 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

Variant3: 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

CaseAddInfo: Suspected Late Onset Pompe Disease, Nomenclature indicates Variants 2 and 3 are in cis

CaseOPOPD-5: Female, 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.503G>C (p.Arg168Pro)

CAID: CA401361673 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.503G%3EC

gnomAD: Not in gnomAD

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

Case5: Male, 18 years diagnosis, 13 years onset

CasePresentingHPOs: HP:0009073, HP:0003198, HP:0003236, HP:0003327 (Progressive proximal muscle weakness, Myopathy, Increased serum CK, Axial muscle weakness)

HPOsFreeText: Electromyography showed myogenic damage, Vacuolar myopathy, Serum CK is 586.2 U/L

Case4: Female, 16 years diagnosis, 13 years onset

CasePresentingHPOs: HP:0009073, HP:0003198, HP:0003236, HP:0003327, HP:0008994 (Progressive proximal muscle weakness, Myopathy, Increased serum CK, Axial muscle weakness, Proximal muscle weakness in lower limbs)

HPOsFreeText: Electromyography showed myogenic damage, Vacuolar myopathy, Serum CK is 1652.0 U/L

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

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

DiseaseAssertion: Pompe disease

FamilyInfo: Patients 2 and 3 are full siblings

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

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

CaseNotHPOs:

CaseNotHPOFreeText: no dysphagia at baseline, no tracheostomy

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

PMID: 31392189

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case16: Female, 9 years onset, 11 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.1629C>G (p.Tyr543Ter)

CAID: CA401367368 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1629C%3EG

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

CaseA1: 26 years onset

CaseAddInfo: Late-Onset Pompe Disease, Sibling of A2

Variant: NM_000152.4:c.1212C>G (p.Asp404Glu)

CAID: CA401365194 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1212C%3EG

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Case22: Male, 16 years onset, 41 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.2109del (p.Tyr703Ter)

CAID: CA891862616 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2109del

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Case13: Male, 9 years onset, 19 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

PMID: 24590251

Gene: GAA

Case11: Female, 48 years onset, 54 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 54, GAA Activity at ~8.5 pmol/min/mg before ERT and ~9 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

Case10: Male, 50 years onset, 52 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 53, GAA Activity at ~13 pmol/min/mg before ERT and ~15 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.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

CaseAddInfo: Late Onset Pompe Disease

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

Case29: Female, 50 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 354 meters, Forced Vital Capacity at 116%

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case37: Female, 62 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 475 meters, Forced Vital Capacity at 94%

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case33: Female, 79 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 312 meters, Forced Vital Capacity at 113%

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.1560C>G (p.Asn520Lys)

CAID: CA401367200 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1560C%3EG

gnomAD: Not in gnomAD

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

Patient4: 3yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20 QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous variant, 6days old at ERT start

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

Patient13: 6yo

CasePresentingHPOs:

HPOsFreeText: rhGAA dosage = 20 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 37mo at ERT start

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_000152.3:c.1781G>A

CAID: CA8815477, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8815477

gnomAD: 1.729e-05, http://exac.broadinstitute.org/variant/17-78086403-G-A

Patient5: 12yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20 EOW, ventilator dependent

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 6mo at ERT start

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_000152.3:c.2023_2025del

CAID: CA274244, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA274244

gnomAD: 2.105e-05, http://exac.broadinstitute.org/variant/17-78086806-CACA-C

Patient9: 2yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 40 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 14days old at ERT start

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.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

Patient8: 2yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 40 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 16 days old at ERT start

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_000152.3:c.1197_1208del

CAID: CA658795246, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795246

gnomAD: n/a

Case#: 84, Gender N/A, 6 months old when diagnosed, Asian

DiseaseAssertion: Pompe disease

FamilyInfo: Both parents were tested for variants in GAA

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient did not present any symptoms, diagnosed was made based on the predicted impact of the variant by PolyPhen-2

CasePreviousTesting: The GAA gene was sequenced using NGS and resequenced for confirmation using Sanger.

Dried Blood spot test found an GAA activity of 3.8 pmol/h/disk with a reference value of 6.5 pmol/h/disk

enzyme activity in fibroblast was recorded to be 3.0 nmol/h/mg protein.

Variants: Variant1: (Two mutated alleles with heterozygous mutations)

Variant1.1: NM_000152.5(GAA):c.752C>T (p.Ser251Leu)

ClinVar: 346310

CAID: CA8815007

gnomAD: Highest population MAF = 0.002234 (East Asian)

Variant1.2: NM_000152.5(GAA):c.761C>T (p.Ser254Leu)

ClinVar: 330447

CAID: CA8815009

gnomAD: Highest popu;ation MAF= 0.002235 (East Asians)

Variant2: C.1244C>T

ClinVar: N/A

CAID: N/A

gnomAD: N/A

ParentalGenotype: The c.752C>T+c.761C>T and c.1244C>T of subject ID 84 were derived from mother and father, respectively

PreviouslyPublished:N/A

Case#: 93, gender N/A, 6months old when diagnosed, Asian

DiseaseAssertion: Pompe disease

FamilyInfo: Both parents were carriers of mutations in the GAA gene. The patient inherited the mutations.

CasePresentingHPOs: N/A

CaseHPOFreeText: Symptoms were noted at the age of 2.7 months old

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient showed no symptoms but LOPD was diagnosed based on the predicted impact of the variants by PolyPhen-2

CasePreviousTesting: The GAA gene was sequenced using NGS and resequenced for confirmation using Sanger.

Dried Blood spot test found an GAA activity of 0.25 pmol/h/disk with a reference value of 6.5 pmol/h/disk

Variant1: NM_000152.5(GAA):c.317G>A (p.Arg106His)

ClinVar: 286481

CAID: CA8814849

gnomAD: MAF=0.0001094 in East Asian

Variant2: (COMBINATION OF MUTATIONS IN THIS ALLELE, DOUBT HERE)

Variant2.1: NM_000152.5(GAA):c.752C>T (p.Ser251Leu)

ClinVar: 346310

CAID: CA8815007

gnomAD: Highest population MAF = 0.002234 (East Asian)

Variant2.2: NM_000152.5(GAA):c.761C>T (p.Ser254Leu)

ClinVar: 330447

CAID: CA8815009

gnomAD: Highest population MAF= 0.002235 (East Asians)

ParentalGenotype: Father is heterozygous for c.317G>A (p.Arg106His).

Mother carries both mutations of c.[752C>T,761C>T].

PreviouslyPublished:N/A

Patient19: 55yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887

HPOsFreeText: morning headache, GAA = 6%, BMI = 25, normal CTA, temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

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

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

gnomAD: n/a

Patient10: 50yo

CasePresentingHPOs: HP:0003325, HP:0004944, HP:0020038

HPOsFreeText: GAA = 3.6%, BMI = 22.4, MCA M1 4mm aneurysm, normal CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk factor

CaseAddInfo: 13yr 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

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

Case7: 0.1 years diagnosis, Germany

CasePresentingHPOs: HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

HPOsFreeText: 56 BNP (pg/ml), 6.01 IVS (d) z score, 6.45 IVS (s) z score, Heart Failure at NYHA Class 1, Left-ventricular outflow tract obstruction

CaseAddInfo: Infantile-Onset Pompe Disease

CaseLOPD-3: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.7%

GenotypingMethod: Newborn Screening Panels

Variant: NM_000152.4:c.2647-7G>A

ClinVar: 551106 https://www.ncbi.nlm.nih.gov/clinvar/variation/551106/

gnomAD: South Asian 3.266e-5, Overall 1.780e-5 http://gnomad.broadinstitute.org/variant/17-78092445-G-A

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseLOPD-7: 24 years diagnosis

CasePresentingHPOs: HP:0003236, HP:0012378, HP:0002910 (Increased serum CK, Fatigue, Elevated transaminases)

HPOsFreeText: GAA activity 4.0 (nmol · h−1 · mg−1), Mean percentage of normal 5.6%

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.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

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

CasePD/VOUS-5: 1.7 years diagnosis

HPOsFreeText: GAA activity 9.16 (nmol · h−1 · mg−1), Mean percentage of normal 12.9%

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.1424C>T (p.Pro475Leu)

CAID: CA8815314 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.1424C%3ET

gnomAD: South Asian 1.307e-4, Overall 2.009e-5 http://gnomad.broadinstitute.org/variant/17-78083841-C-T

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

CasePD/VOUS-7: 3 weeks diagnosis

HPOsFreeText: GAA activity 3.43 (nmol · h−1 · mg−1), Mean percentage of normal 4.8%

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

Multiple interpretations of p.G615R possible

Variant3: NP_000143.2:p.G615R

CAID: PA113309 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NP_000143.2%3Ap.G615R

gnomAD: N/A

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

PMID: 30770309 Gene: GAA

Case#: Patient, female, 61 years old, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0040213, HP:0010535, HP:0003326, HP:0002273, HP:0002877 (Hypopnea, Sleep Apnea, Myalgia, Tetraparesis, Nocturnal hypoventilation)

CaseHPOFreeText: Sleep Apnea-Hypopnea Syndrome (SAHS), predominantly proximal tetraparesis

CaseNotHPOs: N/A

CaseNotHPOFreeText: Serum measurements were normal, includind Creatine Phosphokinase levels (CPK)

CasePreviousTesting: GAA enzyme level 0.72 µkat/kg was significantly reduced in lymphocytes with a reference range of 4.8–13.3 µkat/kg protein. This test was done with maltase-glucoamylase inhibitor acarbose

All exons and flanking introns were bidirectionally sequenced after PCR amplification. "sequence-analysis of GAA transcripts"

Variant: c.1194+5G>A

ClinVar:

CAID:CA658795243

gnomAD:

ParentalGenotype:

PreviouslyPublished: N/A

Patient2: concentration-dependent effects of AONs 3 and 4 confirmed in a fibroblast cell line from this patient, this concluded that these AONs show in vitro activities sufficient to elevate canonical GAA pre-mRNA splicing and thus enzymatic activity

CasePresentingHPOs:

HPOsFreeText:

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: n/a

CaseGenotypingMethod: n/a

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.923A>C

CAID: CA401364056, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401364056

gnomAD: n/a

Patient1: control experiment performed on patient's primary fibroblasts to validate U7 snRNA vector, screen showed multiple U7 snRNA-based AONs that modulate inclusion of exon 2 in GAA mRNA

CasePresentingHPOs:

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: n/a

CaseGenotypingMethod: n/a

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

Case4: Male, 0.8 yr onset, 2 yr diagnosis, 2.4 yr report

HPOsFreeText: 1353 CK U/l, 13 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, no respiratory support

Case13: Male, 5 yr onset, 2 yr diagnosis, 7.6 yr report

HPOsFreeText: Respiratory support at night, FVC z-score sitting -1.77 (78% pred), FVC z-score supine -1.72 (79% pred), 100% MRC Scale, 436 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

CaseHPOFreeText:

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

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

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

PreviouslyPublished: N/A

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

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

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

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

PreviouslyPublished: N/A

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

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

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

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

PreviouslyPublished: N/A

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

CaseHPOFreeText:

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

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

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

PreviouslyPublished: N/A

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

CaseHPOFreeText:

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

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

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

PreviouslyPublished: N/A

Case#: Patient 6, Gender N/A, Onset at 5-6 months. Death around 2 years old, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: P:0001639. HP:0005165, HP:0001270, HP:0011968

(Dyspnea, Shortened PR interval, Motor delay, Feeding difficulties,

CaseHPOFreeText: FTT, BVH, Severe MR)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0.43% of normal control value.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant: NM_000152.5(GAA):c.781G>A (p.Ala261Thr)

ClinVar: 456438

CAID: CA8815016

gnomAD: Highest population MAF = 0.00009799 (South Asian)

ParentalGenotype: Father and Mother were carriers of the variant c.781G>A (p.Ala261Thr)

PreviouslyPublished: N/A

Case#: Patient 10, Gender N/A, Onset at 1-2 months. Death at 10 months, Southeast Asian

DiseaseAssertion:Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639. HP:0005165, HP:0002100

(Dyspnea, Shortened PR interval, Recurrent aspiration pneumonia)

CaseHPOFreeText: BVH, SDD

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting GAA enzyme activity is not available.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant: NM_000152.5(GAA):c.876C>G (p.Tyr292Ter)

ClinVar: 637958

CAID: CA500127534

gnomAD: N/A

ParentalGenotype: Both parents are carriers of the variant c.876C>G (p.Tyr292Ter)

PreviouslyPublished: N/A

Patient1: female, 22 yo, Caucasian

CasePresentingHPOs: HP:0003710, HP:0003326, HP:0040081, HP:0045040, HP:0002910

HPOsFreeText: CK = 571 U/l, LDH = 301 U/l, ASAT = 85 U/l, ALAT = 84 U/l, GAA activity = 0.31nmol/spot x21hrs, small droplet lipid deposits in the muscle fibres of vastus lateralis

CaseNotHPOs: HP:0003457, HP:0009051, HP:0001639, HP:0002111, HP:0002093

NotHPOsFreeText: MRI of thigh muscles showed no abnormalities, no changes in the PAS positive inclusions

CaseAddInfo: 14yo at symptom onset, no family history of neuromuscular disease

CasePreviousTesting: EMG, MRI, 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

Case#: P 2, Female, 4.7 months old when started ERT (113.7 months old at publication date), ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: Table 1 includes parental genotype

CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090

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

CaseHPOFreeText: Aspiration pneumonia was a complication during ERT.

Patient requires tube feeding.

Patient's best and current motor status is being able to sit.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient has not required ventilation

CasePreviousTesting: CRIM status is positive in patient

Antibody titer is 1:1.200

Variant 1: NM_000152.5(GAA):c.1799G>A (p.Arg600His)

ClinVar: 370130

CAID: CA8815482

gnomAD: Highest population MAF= 0.00003267 in South Asians

Variant 2: c.1859G>A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

ParentalGenotype: Mother is the carrier of the c.1799G>A (p.Arg600His) Variant

Father is the carrier of the c.1859G>A variant

PreviouslyPublished: N/A

Case#: P 14, Male, 1.5 months old when started ERT (Died at 41.8 months old), German

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090

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

CaseHPOFreeText: Pneumonia and deterioration were complications during ERT

Required ventilation

CaseNotHPOs: N/A

CaseNotHPOFreeText: Did not required tube feeding

CasePreviousTesting: CRIM Status and Antibody titer are unknown

Variant: NM_000152.5(GAA):c.1978C>T (p.Arg660Cys)

ClinVar:<br /> 558604

CAID: CA8815561

gnomAD: MAF=0.00005554 in East Asian

ParentalGenotype: Both the paternal and maternal allele carry the variant c.1978C>T (p.Arg660Cys)

PreviouslyPublished: N/A

Case#: P 5, Male, 0.9 months old when started ERT (76.9 months old at publication date), Ethnicity unknown

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.

AR III

Patient requires tube feeding and is ventilated

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CRIM status is unknown

Antibody titer is 1:12,000

Variant: NM_000152.5(GAA):c.2662G>T (p.Glu888Ter)

ClinVar: 578595

CAID: CA8815829

gnomAD: Highest population MAF= 0.0002719 (East asian)

ParentalGenotype: Both the paternal and maternal allele carry the c.2662G>T (p.Glu888Ter) Variant

PreviouslyPublished: N/A

Case3: Female, Swedish, 64 years report, 48 years onset

CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)

HPOsFreeText: 6-min walk test achieved 369 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 2.8/2.7 (L), On the medications Zopiklon and Ketoprofen

NotHPOsFreetext: Not on ERT

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

Variant1: NM_000152.4:c.2560C>T (p.Arg854Ter)

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: Late Onset Pompe Disease

Case6: Female, French, 26 years report, 21 years onset

CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)

HPOsFreeText: 6-min walk test achieved 496 m, MRC score is 3/5 (thigh/calf), Forced vital capacity sitting/supine is 2.2/1.9 (L), Has started ERT,On the medication Perindopril

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

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

CAID: CA913184742 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184742

gnomAD: Not in gnomAD

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

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

Patient 5

Variant1: NM_000152.3:c.1396del

CAID: CA658795256, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795256

gnomAD: n/a

Variant2: NM_000152.3:c.1705dup

CAID: CA658795264, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1705dup

gnomAD: n/a

Patient5: IOPD Group, 12days old

CasePresentingHPOs:

HPOsFreeText: LDH = 464 U/L, CK = 380 U/L, ALT = 58 U/L, AST = 100 U/L, Mann-Whitney Test = 2

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Patient3: IOPD Group, 11days old

CasePresentingHPOs:

HPOsFreeText: LDH = 664 U/L, CK = 809 U/L, ALT = 48 U/L, AST = 117 U/L, Mann-Whitney Test = 3

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Patient9: IOPD Group, 14days old

CasePresentingHPOs:

HPOsFreeText: LDH = 597 U/L, CK = 998 U/L, ALT = 43 U/L, AST = 102 U/L, Mann-Whitney Test = 3

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Case#: Patient 4

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

Case#: Patient 8

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: 0.05 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.472A>G

Variant 2 ClinVarID:

Variant 2 CAid: CA401361595

Variant 3: NM_000152.5:c.668G>A

Variant 3 ClinVarID: 92488

Variant 3 CAid: CA145791

Variant 4: NM_000152.5:c.503G>T

Variant 4 ClinVarID:

Variant 4 CAid: CA8814883

ParentalGenotype: Not provided

Case#: Patient 5

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.2560C>T

Variant 1 ClinVarID: 4034

Variant 1 CAid: CA340130

Variant 2: NM_000152.5:c.2446G>A

Variant 2 ClinVarID: 92477

Variant 2 CAid: CA145772

ParentalGenotype: Not provided

Case#: Patient 7

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: 0.05 nmol 5MU/hr/mL

Variant 1: NM_000152.5:c.2560C>T

Variant 1 ClinVarID: 4034

Variant 1 CAid: CA340130

Variant 2: NM_000152.5:c.596A>G

Variant 2 ClinVarID: 92486

Variant 2 CAid: CA145785

Variant 3: NM_000152.5:c.668G>A

Variant 3 ClinVarID: 92488

Variant 3 CAid: CA145791

ParentalGenotype: Not provided

Patient9: Male, <1 year onset

CaseAddInfo: LOPD

Patient7: Female, 1 year onset

CasePresentingHPOs: HP:0002240 (Hepatomegaly)

HPOsFreeText: GAA activity 1% from leukocyte

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

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient3: Female, 6 years report, birth onset

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

HPOsFreeText: GAA activity 2.1% from leukocyte

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: IOPD

Case#: Case 2, male, 50 days old when diagnosed, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0001252, HP:0000282 (cardiomyopathy, muscular hypotonia, facial edema)

CaseHPOFreeText:(Associated to Pompe disease) increased serum CK.

CaseHPOFreeText: (Infussion associated reactions) Generalized rash, cough and bronchospasm

CaseNotHPOs: N/A

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

CasePreviousTesting: See Table 1 for reports on GAA metabolic activity.

GAA activity in dried blood spots is 0 μmol/l/h with a reference range of 1.86–21.9 μmol/l/h

GAA activity on lymphocytes is 0.5 nmol 4 Mu/mg prot/h with a reference range of 21.4 ± 6.2 nmol 4 Mu/mg prot/h

Variant: c1124G>T (p.R375L)

ClinVar: N/A

CAID: N/A

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient35: male, Caucasian

CasePresentingHPOs: HP:0003676, HP:0003236, HP:0003325, HP:0008994, HP:0003458, HP:0003560, HP:0030121

HPOsFreeText: CK < 10x increase, difficulty ascending stairs, inability to stand without aid, treated with ERT

CaseNotHPOs: HP:0002093

CaseAddInfo: onset as young adult. Older sister also affected with onset at 21 yo. She now exhibits scoliosis, fatigability, paraspinal muscle atrophy, proximal upper limp atrophy, and weakness. Calpain deficiency detected via immunoblot could be connected to CAPN3 variants (p.Gly333Asp [c.998G > A] and p.Ala726Ser [c.2176G > T]).

CasePreviousTesting: same as group, EMG, muscle biopsy, immunoblot analysis

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.569G>A (p.Arg190His)

ClinVar: 188809, https://www.ncbi.nlm.nih.gov/clinvar/variation/188809/

gnomAD: 8.276e-06, http://exac.broadinstitute.org/variant/17-78079570-G-A

Variant2: NM_000152.3:c.2020C>G

CAID: CA401370092, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370092

gnomAD: n/a

Case#: Subject number 10, male, 70 years (report), 58 years (onset), 65 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000365 (hearing loss)

CaseHPOFreeText: on BiPAP, ambulatory, assistive device (walking stick occasionally)

CaseNotHPOs: HP:0000360, HP:0000821, HP:0002650, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0001638 (tinnitus, hypothyroidism, scoliosis, aneurysm, osteoporosis, peripheral neuropathy, 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.2655_2656delCG (p.Val886GlufsTer2)

Variant 2 ClinVarID: 597005

Variant 2 CAid: CA913191011

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 18, male, 65 years (report), 40 years (onset), 62 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000365 (hearing loss), HP:0000939 (osteoporosis), HP:0001638 (cardiomyopathy)

CaseHPOFreeText: ambulatory, on BiPAP

CaseNotHPOs: HP:0000360, HP:0000821, HP:0002650, HP:0002617, HP:0009830, HP:0100647, HP:0010788 (tinnitus, hypothyroidism, scoliosis, aneurysm, peripheral neuropathy, Graves disease, Testicular cancer)

CaseNotHPOFreeText: no tracheostomy, no infusion reaction

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.1051delG

Variant 2 ClinVarID: 188841

Variant 2 CAid: CA274024

Zygosity: Compound heterozygous

ParentalGenotype: N/A

Case#: Subject number 6, female, 57 years (report), 20s years (onset), 31 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002650 (scoliosis)

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

CaseNotHPOs: HP:0000360, HP:0000365, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0000821, HP:0001638 (tinnitus, hearing loss, aneurysm, osteoporosis, peripheral neuropathy, Graves disease, Testicular cancer, hypothyroidism, 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.925G>A (p.Gly309Arg)

Variant 2 ClinVarID: 188797

Variant 2 CAid: CA273972

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 2, male, 48 years (report), 39 years (onset), 43 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002617 (aneurysm)

CaseHPOFreeText: on BiPap, ambulatory

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

CaseNotHPOFreeText: No infusion reaction, no tracheostomy

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