Patient7: 71yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0000822, HP:0003141, HP:0002870, HP:0020038

HPOsFreeText: morning headache, GAA = 7%, BMI = 28.3, temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 18yr 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

Patient5: 36yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0001513, HP:0002637

HPOsFreeText: GAA = 4.6%, BMI = 35.1, normal CTA, right temporal pole ischaemia

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 4yr 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

Patient21: 68yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0003141, HP:0001513, HP:0020038

HPOsFreeText: GAA = 30%, BMI = 30.3, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 30yr 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

Patient8: 47yo

CasePresentingHPOs: HP:0003325, HP:0001513

HPOsFreeText: GAA = 5%, BMI = 30.8, Normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2yr 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

Patient6: 47yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0020038

HPOsFreeText: GAA = 7%, BMI = 27.5, normal CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 14yr disease duration, variants in trans

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_000152.3:c.2530_2541del

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

gnomAD: n/a

Patient18: 40yo

CasePresentingHPOs: HP:0003325

HPOsFreeText: GAA = 5%, smoker, BMI = 16.3, normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 4yr 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

Patient2: 76yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0000822, HP:0002870, HP:0020038

HPOsFreeText: morning headaches, GAA = 13%, BMI = 23.6, right vertebral artery dominant, nucleo-capsular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 33yr 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

Patient9: 54yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0003141, HP:0002870

HPOsFreeText: morning headache, GAA = 7%, smoker, BMI = 23.3, normal CTA, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 29yr 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

Patient1: 40yo

CasePresentingHPOs:

HPOsFreeText: HyperCKemia, GAA = 4%, BMI = 25.8, normal CTA, temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText: no cardiovascular risk factor

CaseAddInfo: 6yr 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

Patient15: 53yo

CasePresentingHPOs: HP:0002315, HP:0004887, HP:0000822, HP:0003141, HP:0002870, HP:0020038

HPOsFreeText: hyperCKema, morning headaches, GAA = 13%, BMI = 29.6, right ventricular artery dominant, Normal CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr disease duration, homozygous variants in trans

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

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

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

GroupPresentingHPOs: HP:0003325, HP:0003457, HP:0012548, HP:0004887, HP:0010535, HP:0001712, HP:0031296

HPOsFreeText: hyperCKaemia+LGMW, BMI, mean (SD) 25.2±5.8, Serum CK, mean (SD) 600±302, vacuolar myopathy, Muscle GAA %, mean (SD) 9.4±3.8, myogenic EMG, abnormal MRI, %Predicted FVC, mean (SD) 73±11, 6MWT, mean (SD) 452±9, vacuolisation of myofibers with variable glycogen storage, AP staining low in 6 individuals, medium in five, and high in 2 individuals. Low residual GAA activity in muscles,

GroupNotHPOs:

NotHPOsFreeText:

NumberMales: 8

NumberFemales: 9

CountryOrigin: n/a

AgeRange: mean (SD) 40±14.36

TotalNumber: 14

GroupAddInfo: mean age at disease onset was 40±14.3 years, median age at disease diagnosis was 47±14 years. 14 of the individuals underwent enzyme replacement therapy. Blood CK levels increased in all but one individual.

GroupGenotypingMethod: GAA gene sequencing

Variant 1: 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

Variant 2: p.P522A, NM_000152.4(GAA):c.1564C>G (p.Pro522Ala)

ClinVar: 371277, https://www.ncbi.nlm.nih.gov/clinvar/variation/371277/

gnomAD: n/a

Family 10 - Patient 10

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0003327, HP:0040081, HP:0002111

HPOsFreeText: muscle pathology with vacuolar myopathy

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003691, HP:0003306, HP:0002650

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: onset at 38yo, diagnosis at 50yo, MRC sum score = 73, patient required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: FVC = 65%, CK = 551 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 0.12 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_000152.3:c.2596delG

CAID: CA891834514, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA891834514

gnomAD: n/a

Family 4 - Patients 4a and 4b

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0010628, HP:0002015, HP:0003306, HP:0002111, HP:0011807, HP:0003554, HP:0002111, HP:0100298, HP:0040081

HPOsFreeText: myopathic muscle unit action potentials, 4b muscular pathology with mild atrophy of type 1 and 2 fibers with many moth‐eaten fibers, no vacuoles, no glycogen excess

FamilyNotHPOs: HP:0003691, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel: 4a, female, 7yo at onset, 30yo at diagnosis

FamilyAddInfo: 4b (male) dx at 23yo, 4a MRC sum score = 84, 4b MRC sum score = 86, both patients required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: 4a FVC = 29%, 4b FVC = 66%, 4a CK = 760 U/L, 4b CK = 3,257 U/L, muscle pathology (examined only in 4b), DBS enzyme activity (with inhibition) for 4a = 0.1 μmol/L/h, for 4b = 0.13 μmol/L/h, NCS, EMG

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_000152.3:c.1650delG

Clinvar: n/a

CAID: CA627699787, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA627699787

gnomAD: n/a

Family 2 - Patient 2

FamilyPresentingHPOs: HP:0002355, HP:0003701, HP:0000467, HP:0009027, HP:0010628, HP:0002015, HP:0002111

HPOsFreeText:

FamilyNotHPOs: HP:0003691, HP:0003306, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel: Patient 2, male

FamilyAddInfo: 2yo at onset, 9yo at diagnosis MRC sum score = 73, NIV prescribed due to reduced FVC

FamilyPreviousTesting: Respiratory evaluation: FVC = 23%, CK = 83 U/L, Normal muscle pathology exams, DBS enzyme activity (with inhibition) = 0.14 μmol/L/h

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

Variant: NM_000152.3:c.2040+2dup

ClinVar: n/a

CAID: CA891834512, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA891834512

gnomAD: n/a

Family 5 - Patients 5a and 5b

FamilyPresentingHPOs: HP:0009027, HP:0000467, HP:0003327, HP:0003691, HP:0002650, HP:0040081, HP:0100284

HPOsFreeText: Myotonic discharges in paraspinal, tibialis anterior, first dorsal interosseous, and biceps muscles, Myopathic muscle unit action potentials, 5b muscular pathology with Severe lysosomal vacuolar myopathy with prominent glycogen excess

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003306

Ethnicity: Iranian

ProbandLabel: 5a, male, 10yo at onset, 12yo at diagnosis

FamilyAddInfo: 5b (female) dx at 15 yo, 5a MRC sum score = 94, 5b MRC sum score = 91

FamilyPreviousTesting: Respiratory Evaluation: 5a FVC = 91%, 5b FVC = 106%, 5a CK = 1,202 U/L, 5b CK = 907 U/L, muscle pathology (examined only in 5b), DBS enzyme activity (with inhibition) for 5a = 0.5 μmol/L/h, for 5b = 0.6 μmol/L/h, NCS, EMG

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

Variant: NM_000152.3:c.1837T>G

ClinVar: n/a

CAID: CA401369569, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369569

gnomAD: n/a

CaseP5-GAA: female, ethnicity = South Asian, country origin = Nepal

CasePresentingHPOs:

HPOsFreeText: enzyme activity = 2.27

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

CaseAddInfo: known pseudodeficiency allele (c.1726G>A)

CasePreviousTesting: initial and confirmatory DBS, biochemical tests

CaseGenotypingMethod: mutation analyses

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

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

gnomAD: n/a

CaseP4-GAA: female, ethnicity = European, country origin = Italy

CasePresentingHPOs:

HPOsFreeText: enzyme activity = 2.22

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

CaseAddInfo: homozygous

CasePreviousTesting: initial and confirmatory DBS, biochemical tests

CaseGenotypingMethod: mutation analyses

Variant: NM_000152.4(GAA):c.533G>A (p.Arg178His)

ClinVar: 554969; https://www.ncbi.nlm.nih.gov/clinvar/variation/554969/

gnomAD: 2.646e-05, http://exac.broadinstitute.org/variant/17-78078918-G-A

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

Patient13: Male, 46yo at diagnosis, 47yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:25,699, enzyme (μmol/g/h) = 0.52 (3-20)

CaseNotHPOs:

NotHPOsFreeText: NIV and mobility aid not required

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.482_483del

CAID: CA8814879, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8814879

gnomAD: 1.729e-05, http://exac.broadinstitute.org/variant/17-78078864-TCC-T

Patient16: Female, 37yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 0.18 (3-20), mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: NIV not required

CaseAddInfo: 21yr 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

Patient1: Female, 37yo at diagnosis, 38yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:800, Enzyme = 0.3 (3-20) μmol/g/h, NIV used before and after ERT, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 23yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4:c.1040C>G

CAID: CA401364692, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1040C%3EG

gnomAD: n/a

Variant2: c.1559A > I believe this paper had a typo so I was unable to find this variant in both ClinVar and the allele registry

Patient2: Male, 40yo at diagnosis, 63yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies tire = 1:6400, enzyme (μmol/g/h) = 0.36 (3-20), NIV used before and after ERT

CaseNotHPOs:

NotHPOsFreeText: mobility aid not used

CaseAddInfo: 23yr 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.2135T>C

CAID: CA401370560, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2135T%3EC

gnomAD: n/a

Patient8: Female, 41yo at diagnosis, 48yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:1600, enzyme (μmol/g/h) = 0.23 (2-10), mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: NIV not required

CaseAddInfo: 7yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.482_483del

CAID: CA8814879, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8814879

gnomAD: 1.729e-05, http://exac.broadinstitute.org/variant/17-78078864-TCC-T

Variant2: NM_000152.4(GAA):c.692+5G>T

ClinVar: 562532, https://www.ncbi.nlm.nih.gov/clinvar/variation/526532/

gnomAD: 8.596e-06, http://exac.broadinstitute.org/variant/17-78079698-G-T

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

Subject II-3: male

CasePresentingHPOs:

HPOsFreeText: altered DBS, reduced GAA activity

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: DBS

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

Subject III-10: female

CasePresentingHPOs:

HPOsFreeText: DBS neutral/acid = 38.1

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: asymptomatic, asserted carrier status

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA genotyping

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

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

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

Subject III-9: Female

CasePresentingHPOs:

HPOsFreeText: DBS neutral/acid = 36.0

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: asymptomatic, asserted carrier status

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA Genotyping

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

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

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

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

Subject II-4: female

CasePresentingHPOs:

HPOsFreeText: normal GAA enzyme values

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: carrier status, clinically asymptomatic

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA genotyping

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

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

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

Patient5: male, Romanian

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325, HP:0003418, HP:0008997

HPOsFreeText: CK > 10x increase, CK = 1500 U/L, reduced alpha-glucosidase activity

CaseNotHPOs: HP:0002093

CaseAddInfo: onset in middle age, enzyme activity also reduced in daughter

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2066_2070dupAGCCG (p.Ala691Serfs)

ClinVar: 92471, https://www.ncbi.nlm.nih.gov/clinvar/variation/92471/

gnomAD: n/a

Variant2: 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

Patient18: female, White British

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325, HP:0003701, HP:0003458, HP:0003715, HP:0030231

HPOsFreeText: CK > 10x increase, CK = 599 U/L. Vacuolated, degenerated, and atrophic fibers. Vacuole periphery showed abnormal immunoreactivity for desmin and p62. Z-band streaming of fibers, granular material accumulation. Treated with ERT. Normal to low alpha-glucosidase activity.

CaseNotHPOs: HP:0002093

NotHPOsFreeText: no evidence of glycogenosis

CaseAddInfo: onset after 50yo

CasePreviousTesting: same as group, muscle biopsy, NADH-tetrazolim reductase staining

CaseGenotypingMethod: same as group

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

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

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

Variant2: 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

Patient32: Male, Caucasian, first investigated at 15yo

CasePresentingHPOs: HP:0003677, HP:0002111, HP:0002875, HP:0003458

HPOsFreeText: CK < 10x increase, CK = 662 U/L. Reduced alpha-glucosidase activity.

CaseNotHPOs: HP:0003325, HP:0002093

CaseAddInfo: onset in childhood, confirmed Pompe Disease via Sanger Sequencing, 2 siblings also carried same variants and presented with reduced enzyme activity but were asymptomatic at time of study.

CasePreviousTesting: same as group, muscle biopsy, EMG

CaseGenotypingMethod: same as group

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

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

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

Variant2: 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

Patient17: Male, Caucasian

CasePresentingHPOs: HP:0003678, HP:0002093, HP:0003325, HP:0003701, HP:0003388, HP:0002111, HP:0003458

HPOsFreeText: normal CK levels, back muscle weakness, variability in muscle fibre diameter and glycogen accumulation. Slightly reduced alpha-glucosidase activity. Treated with ERT.

CaseNotHPOs: HP:0003236

CaseAddInfo: onset as a young adult, Pompe confirmed via Sanger Sequencing and DBS results.

CasePreviousTesting: same as group, EMG, muscle biopsy

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.1192delC

CAID: CA628018372, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA628018372

gnomAD: n/a

Variant2: NM_000152.3:c.2716G>A

CAID: CA401326980, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401326980

gnomAD: n/a

Case: Male, Spanish, onset at 57yo with pelvic weakness

CasePresentingHPOs: HP:0003236, HP:0002522, HP:0003184, HP:0012515, HP:0003749, HP:0003700, HP:0005144, HP:0002151, HP:0030232, HP:0009058

HPOsFreeText: weakness of hip adduction and shoulder abduction, abolished lower limb reflexes. CK = 500-800 U/L, lactate = 27.0 U/L, GOT = 50 U/L, GPT = 69 U/L, LDH = 449 U/L, aldolase = 8.7 U/L, myopathic motor unit action potentials with early recruitment and spontaneous activity (mainly in quadriceps), asymmetric septal left ventricular hypertrophy with preserved ventricular function, atrophy of both biceps and deltoid muscles, fibrillary deposits in cytoplasm, focal disorganization of sarcomeres, decrease in GAA inhibitory activity (0.64-0.68 μmol/L/h)

CaseNotHPOs: HP:0001283, HP:0002093, HP:0003326, HP:0002487

NotHPOsFreeText:

CaseAddInfo: daughter also underwent genetic testing which showed she was a heterozygous carrier for the same variant. She presented with decreased GAA activity in DBS and isolated lymphocytes.

CasePreviousTesting: blood laboratory exams, electromyography study, echocardiogram, biopsy of biceps and deltoid muscles, histochemical staining which showed no abnormalities, electron microscopy, DBS, enzyme activity analyzed in isolated lymphocytes (confirmed decreased GAA activity)

CaseGenotypingMethod: n/a

Variant: NM_000152.3:c.1249A>C

CAID: CA401365271, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401365271

gnomAD: n/a

GroupPresentingHPOs: HP:0003701, HP:0003327, HP:0003325, HP:0003236

HPOsFreeText: average GAA activity with inhibitor of 0.18 nmol/punch × 21 hours

GroupNotHPOs: n/a

NotHPOsFreeText: n/a

NumberMales: 32 (44%)

NumberFemales: 42 (56%)

CountryOrigin: n/a

Ethnicity: n/a

Race: n/a

AgeRange: 18-81 years, median = 48 years

TotalNumber: 74

FamilyInfo: n/a

NoFamily: n/a

GroupPreviousTesting: DBS collected from peripheral vein analyzed with fluorometric assay

GroupGenotypingMethod: Sanger sequencing of coding and exon flanking region of GAA gene

Variant Count: 74

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: male, gestational age of 37 weeks and 4 days, birth weight = 3.640kg

CasePresentingHPOs: HP:0001639, HP:0030148, HP:0200128, HP:0001640, HP:0003236, HP:0002910, HP:0002788, HP:0001522, HP:0009051

HPOsFreeText: ventricular septal thickness = 11mm, left ventricular posterior wall thickness = 8-9mm (higher at apical level), CK = 4168 UI/L, glutamic oxaloacetic transaminase = 250 UI/L, normal brain and abdominal ultrasounds, GAA activity = 0.9 μmol/L/h, CRIM positive, treated with ERT and beta-blockers, subsarcolemmal vacuolization of the cardiac muscle, moderate vacuoles in skeletal and smooth muscle, neurons, and glial cells due to glycogen accumulation

CaseNotHPOs: HP:0006673, HP:0001941, HP:0001943

CaseAddInfo: diagnosis of HCM at 48hrs of life, non consanguineous Nigerian parents, no family history of heart disease, admitted to hospital at 2 months due to upper respiratory infection, death due to ventricular fibrillation during central line placement procedure

CasePreviousTesting: (2D) echocardiogram, EKG, laboratory tests, brain and abdominal ultrasounds, DBS

CaseGenotypingMethod: n/a

Variant: 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

Patient1: the efficacy of AMOs 1, 2, and 3 were tested in cultured fibroblasts from this patient

Under basal conditions, the fibroblasts retained 20% enzymatic activity compared to WT cells; treatment with combination of the AMOs showed rescue of normally spliced GAA mRNA, this was confirmed with real-time qPCR

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: unknown

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

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

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

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

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

CaseNotHPOs: HP:0001627

NotHPOsFreeText:

CaseAddInfo:

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

CaseGenotypingMethod: full sequencing of GAA gene

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

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

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

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

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

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