Case19: Male, 15 years onset, 15.5 years diagnosis, 15 years report

CasePresentingHPOs: HP:0003236 (Increased serum CK)

HPOsFreeText: Asymptomatic hyperCKemia

CaseAddInfo: Late-Onset Pompe Disease

Case21: 12.5 years onset, 13 years diagnosis, 13 years report

CasePresentingHPOs: HP:0003236 (Increased serum CK)

HPOsFreeText: Asymptomatic hyperCKemia

CaseAddInfo: Late-Onset Pompe Disease, Gender reported as "W"

CaseC: Female, 2 months onset, 3 months diagnosis

CasePresentingHPOs: HP:0001270, HP:0003324, HP:0001638 (Motor delay, Generalized weakness, Cardiomyopathy)

HPOsFreeText: CRIM positive

CaseNotHPOs: HP:0100543, HP:0002540, HP:0004887 (Cognitive impairment, Inability to walk, Respiratory failure requiring assisted ventilation)

CaseAddInfo: Infantile-Onset Pompe Disease

CasePD/Pathogenic-5: 4 weeks diagnosis

HPOsFreeText: GAA activity 6.5 (nmol · h−1 · mg−1), Mean percentage of normal 9.1%

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.-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

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

CaseIOPD-2: 10 days diagnosis

CasePresentingHPOs: HP:0003236, HP:0001638 (Increased serum CK, Cardiomyopathy)

HPOsFreeText: GAA activity 1.8 (nmol · h−1 · mg−1), Mean percentage of normal 1.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.854C>G (p.Pro285Arg)

ClinVar: 225114 https://www.ncbi.nlm.nih.gov/clinvar/variation/225114/

gnomAD: European (Non-Finnish) 1.148e-5, Overall 5.109e-6 http://gnomad.broadinstitute.org/variant/17-78081517-C-G

Variant2: NM_000152.4:c.2303C>T (p.P768L)

CAID: CA401324900 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.2303C%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

CaseLOPD-5: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.1 (nmol · h−1 · mg−1), Mean percentage of normal 4.4%

GenotypingMethod: Newborn Screening Panels

Variant: 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

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

CaseLOPD-1: 3 weeks diagnosis

HPOsFreeText: GAA activity 3.2 (nmol · h−1 · mg−1), Mean percentage of normal 4.5%

GenotypingMethod: Newborn Screening Panels

Variant: 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

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

CaseIOPD-4: 3 min diagnosis

CasePresentingHPOs: HP:0003236, HP:0001638 (Increased serum CK, Cardiomyopathy)

HPOsFreeText: GAA activity 0.6 (nmol · h−1 · mg−1), Mean percentage of normal 0.9%

GenotypingMethod: Newborn Screening Panels

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

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

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

Variant2: NM_000152.4:c.307T>G (p.Cys103Gly)

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

gnomAD: European (non-Finnish) 7.874e-6, Overall 3.578e-6 http://gnomad.broadinstitute.org/variant/17-78078692-T-G

Variant3: NM_000152.4:c.1000G>T (p.Gly334Cys)

ClinVar: 284864 https://www.ncbi.nlm.nih.gov/clinvar/variation/284864/

gnomAD: Not in gnomAD

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

PMID: 30371346

Gene: GAA

Case#: V.4, female, age of diagnosis 7 months, Moroccan

DiseaseAssertion: Pompe disease

FamilyInfo: Pedigree (figure 2). V.4 parents are cousins (IV.2 and IV.3). V.4 had a cousin (V.3) that died at 8 months of age and was diagnosed with HCM. V.3 parents (IV.1 and IV.4) are cousins. IV.2, IV.3, IV.1 and IV.4 were all heterozygous for the GAA mutation c.236_246del (p.Pro79ArgfsX13). V.4 was homozygous for the mutation.

CasePresentingHPOs: HP:0005157, HP:0001290

(Concentric hypertrophy, generalized hypotonia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: hypotonia without facial dysmorphia or other associated abnormalities.

The heart was structurally normal and no valvular anomalies were observed.

CasePreviousTesting: whole exome sequencing (WES), Sanger sequencing. No metabolic screening was performed.

Molecular analysis of SMN gene excluded Spinal muscular atrophy, one of the major causes of neonatal hypotonia in Morocco.

Variant: NM_000152.5 c.236_246del (p.Pro79ArgfsX13)

ClinVar: 371302

CAID: CA16041880

gnomAD: N/A

ParentalGenotype: Both parents are heterozygous for .236_246del (p.Pro79ArgfsX13)

PreviouslyPublished: N/A

Case#: Patient 3, Gender unknown, age unknown, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0003756

(Cardiomyopathy, Skeletal myopathy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sequence analysis of the GAA gene was performed in a CLIA and CAP certified laboratory. Cross Reactive Immune reaction was indeterminate in peripheral blood mononuclear cells (PBMCs)

Cross Reactive Immune reaction was negative in Dried blood spots.

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)Cite this record

ClinVar: 4034

CAID: CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype: N/A

PreviouslyPublished:N/A

Case#: 5/a, age 29, no age of report

DiseaseAssertion: N/A

FamilyInfo: Family 6, no further information

CasePresenting HPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Family Screening

Variants:

Variant 1: NM_000152.5:c.1921C>G

ClinVar: N/A

CAID: CA401369888

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

ClinVar: 4027

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case52

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.2015G>T (p.Arg672Leu)

CAID: CA401370075 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2015G%3ET

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.2783A>G (p.Tyr928Cys)

CAID: CA401327377 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2783A%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Juvenile Late Onset Pompe Disease

Case45

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.1880C>T (p.Ser627Phe)

CAID: CA294896504 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1880C%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case57

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.1396_1397insG (p.Val466fs*39)

CAID: CA627699396 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1396_1397insG

gnomAD: South Asian 3.271e-5, Overall 4.003e-6 http://gnomad.broadinstitute.org/variant/17-78083807-A-AG

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

Case89

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.877G>A (p.Gly293Arg)

ClinVar: 4036 https://www.ncbi.nlm.nih.gov/clinvar/variation/4036/

gnomAD: Latino 5.704e-5, Overall 1.807e-5 http://gnomad.broadinstitute.org/variant/17-78081617-G-A

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

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

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

CaseAddInfo: Adult Late Onset Pompe Disease

CaseIP2-10: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.09 umol/hr/L, Serum CK at 483 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

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

CaseLP2-3: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.42 umol/hr/L, Serum CK at 140 U/L

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

CasePDC-2: Male, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.84, MS/MS ennzyme activity at 1.34

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.3:c.693-5C>T

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

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

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

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

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

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

CaseOPOPD-71: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.99 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.2431dupC (p.Leu811Profs*?)

CAID: CA658795289 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2431dupC

gnomAD: Not in gnomAD

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-77: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.61 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.2014C>T (p.Arg672Trp)

ClinVar: 188773 https://www.ncbi.nlm.nih.gov/clinvar/variation/188773/

gnomAD: South Asian 3.355e-5, Overall 8.290e-6 http://gnomad.broadinstitute.org/variant/17-78086800-C-T

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

CaseOPOPD-9: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.68 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

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

ClinVar: 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.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-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.61, MS/MS ennzyme activity at 0.01

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.1075+1G>T

CAID: CA401364842 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1075%2B1G%3ET

gnomAD: Not in gnomAD

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

Variant: NM_000152.4:c.2460dup (p.Gly821Trpfs*63)

CAID: CA891862618 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2460dup

gnomAD: Not in gnomAD

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

Case18: Female, 16 years onset, 19 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.-32-1G>C

ClinVar: 557429 https://www.ncbi.nlm.nih.gov/clinvar/variation/557429/

gnomAD: Not in gnomAD

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

Case14: Male, 2 years onset, 3 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

CaseD: 17 years onset

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.1754+1dup

CAID: CA891862615 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1754%2B1dup

gnomAD: Not in gnomAD

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

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

Patient18: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

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

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

gnomAD: n/a

Case#: Subject number 7, male, 50 years (report), 32 years (onset), 38 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000365 (hearing loss)

CaseHPOFreeText: on BiPAP, ambulatory

CaseNotHPOs: HP:0002650, HP:0000360, HP:0002617, HP:0000939, HP:0009830, HP:0100647, HP:0010788, HP:0000821, HP:0001638 (scoliosis, tinnitus, 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 4, male, 34 years (report), 5 years (onset), 30 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002650 (scoliosis)

CaseHPOFreeText: on BiPAP, ambulatory

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.258dupC (p.Asn87GlnfsTer9)

Variant 2 ClinVarID: 282842

Variant 2 CAid: CA8814826

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 11, male, 68 years (report), 30s years (onset), 55 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0000360 (tinnitus), HP:0002650 (scoliosis), HP:0000939 (osteoporosis), HP:0000821 (hypothyroidism)

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

CaseNotHPOs: HP:0000365, HP:0002617, HP:0009830, HP:0100647, HP:0010788, HP:0001638 (hearing loss, aneurysm, 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.1951_1952delGGinsT (p.Gly651SerfsTer?)

Variant 2 ClinVarID: 633225

Variant 2 CAid: CA913191010

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 13, male, 50 years (report), 42 years (onset), 45 years (diagnosis)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

*CasePresentingHPOs:* HP:0000360 (tinnitus), HP:0002650 (scoliosis), HP:0001638 (cardiomyopathy), HP:0001638 (Graves disease), HP:0010788 (testicular cancer), HP:0000821 (hypothyroidism)

CaseHPOFreeText: on BiPAP, ambulatory

CaseNotHPOs: HP:0009830, HP:0000939, HP:0000365, HP:0002617 (peripheral neuropathy, osteoporosis, hearing loss, aneurysm)

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.525_526delTG (p.Asn177ProfsTer11)

Variant 2 ClinVarID: 189057

Variant 2 CAid: CA274328

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient6: Male, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1115A>T (p.His372Leu)

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

gnomAD: n/a

Variant2: NM_000152.3:c.2563G>C

CAID: CA401326195, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401326195

gnomAD: 0.00003188, http://gnomad.broadinstitute.org/variant/17-78092073-G-C

Patient6: Female, 53yo

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

HPOsFreeText: LOPD, smoker

CaseNotHPOs:

NotHPOsFreeText:

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

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Variant2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

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

gnomAD: n/a

Case#: Patient 5, male, diagnosed 2010 (not given age of diagnosis), age 44 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: None given

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>A (unclear variant nomenclature)

Variant 1 ClinVarID: N/A

Variant 1 CAid: CA913184742

Variant 2: NM_000152.5:c.2331+2T>G

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA401324960

ParentalGenotype: Not provided

Case#: Patient 9, female, diagnosed 2014 (not given age of diagnosis), age 34 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: None given

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>G (unclear variant nomenclature)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:c.1802C>T

Variant 2 ClinVarID: 194154

Variant 2 CAid: CA274982

ParentalGenotype: Not provided

Case#: Subject number 17, male, 64 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003326 (Myalgia), HP:0002015 (dysphagia)

CaseHPOFreeText:

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

CaseNotHPOFreeText: no biopsy, not asymptomatic

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

glucosidase activity: GAA activity was 0.54 mol/Lh in dried blood spots (normal range >0.75).

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

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.875A>G (p.Tyr292Cys)

Variant 2 ClinVarID: 370577

Variant 2 CAid: CA16041886

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 12, male, 52 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

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

glucosidase activity: GAA activity was 0.48 mol/Lh in dried blood spots (normal range >0.75).

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

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1889-1G>A

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA401369820

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case2: Male, 46 years onset, 46 years diagnosis, 71 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 66 years, Started invasive ventilation at 47 years, Started ERT given every other week at a dose of 20 mg/kg at 66 years for 54 months, Peak Anti-rhGAA antibodies at 1:51,200, FVC at 0.63/16 (L / % expected), MIP at 28 (cm H2O), MEP at 33 (cm H2O), Time off ventilation decreased from 240 to 120 (min/24 h), Total Motor Function Measure from 41 to 44, 6MWT from 20 to 100 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

Case#: Subject number 9, female, 29 years (diagnosis), 55 years (baseline visit), 48 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

PMID: 33732206

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

Case#: Subject number 35, female, 35 years (diagnosis), 35 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

PMID: 31467850

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

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

Patient8: Female, Serbian, mid 70s

CasePresentingHPOs: HP:0003325

HPOsFreeText: Normal CK levels

CaseNotHPOs: HP:0003236, HP:0002093

CaseAddInfo: late onset

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.2051C>G

CAID: CA401370340, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370340

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

Patient8: Female, 4.6mo at ERT start, 3.4yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 40mg/kg/wk ERT, patient had 5 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.378_379del

CAID: CA658795227, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795227

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2104C>T (p.Arg702Cys)

ClinVar: 189040, https://www.ncbi.nlm.nih.gov/clinvar/variation/189040/

gnomAD: n/a

Case1: Male, 42 years diagnosis, 1 year 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 1325.6 U/L

Case13HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.5 mU/U hexosaminid, GAA activity at 17.5% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

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

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

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

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

Variant2: NM_000152.4:c.2482_2646del165 (p.Gly828_Asn882del) (Exon 18 del)

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

gnomAD: Not in gnomAD

CaseAddInfo: Patient is heterozygous for these variants

Case7: Female, 58 years report

HPOsFreeText: 9 years of ERT completed, Forced Vital Capacity at 14%

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.2041-1G>A

CAID: CA8815596 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2041-1G%3EA

gnomAD: European (Non-Finnish) 1.012e-5, Overall 4.541e-6 http://gnomad.broadinstitute.org/variant/17-78087016-G-A

CaseAddInfo: Late Onset Pompe Disease

Case6: Male, 65 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 95 meters, Forced Vital Capacity at 36%

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

Case20: Female, 63 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 10 meters, Forced Vital Capacity at 57%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.1748C>T (p.Ser583Phe)

CAID: CA401369174 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1748C%3ET

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.2014C>T (p.Arg672Trp)

ClinVar: 188773 https://www.ncbi.nlm.nih.gov/clinvar/variation/188773/

gnomAD: South Asian 3.355e-5, Overall 8.290e-6 http://gnomad.broadinstitute.org/variant/17-78086800-C-T

CaseAddInfo: Late Onset Pompe Disease

PMID: 25626711

Gene: GAA

Case#: P 10, Male, 7.0 months old when started ERT (Died at 21.1 months old)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

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

CaseHPOFreeText: Patient required tube feeding

Recurrent pneumonia was a complication during ERT

Patient did not achieved motor function

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient was not ventilated

CasePreviousTesting: CRIM status was unknown

Antibody titer was not available

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID: CA340130

gnomAD: Highest population MAF = 0.001891 (African)

ParentalGenotype: Both the paternal and maternal allele carried the c.2560C>T (p.Arg854Ter) Variant

PreviouslyPublished: N/A

Patient 8 - homozygous

Variant: NM_000152.3:c.1844G>A

CAID: CA401369598, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369598

gnomAD: 0.000004098, http://gnomad.broadinstitute.org/variant/17-78086466-G-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

Case#: Subject number 26(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

glucosidase activity: GAA activity #2 (NBS) 1.01 in dried blood spots (>2.10 micromole/L/h 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.2238G>C

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 14(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 467 U/L (60-305 U/L is normal), AST: 166 U/L (20-64 U/L is normal), ALT: 73 U/L (12-42 U/L is normal), Hex4: 7.0 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.68 micromole/L/h and GAA activity #2 (NBS) 0.79 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.156_157delTC

Variant 1 ClinVarID: N/A

Variant 1 CAid: CA294886619

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 1(I), male, 21 days (start of ERT), 31 months (report)

DiseaseAssertion: Infantile Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002870 (obstructive sleep apnea), HP:0001639 (hypertrophic cardiomyopathy), HP:0200128 (biventricular hypertrophy), HP:0030234 (Highly elevated creatine kinase)

CaseHPOFreeText: moderately to severely decreased left ventricular systolic wall motion, moderate hypertrophy of the left ventricle, severe right ventricular hypertrophy, requires BiPAP at night, patient receives physical, occupational, and speech therapies.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 923 U/L (60–305 U/L is normal), AST: 103 U/L (30–100 U/L is normal), BNP: 1080 pg/mL (0.0–100.0 pg/mL), Hex4: 24.7 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 0.65 micromole/L/h and GAA activity #2 (NBS) 0.22 in dried blood spots (>2.10 micromole/L/h is normal). 4.4 in confirmatory testing (>6.7 is normal).

Variant 1: NM_000152.5(GAA):c.759delC

Variant 1 ClinVarID: 837937

Variant 1 CAid: CA916082438

Variant 2: NM_000152.5(GAA):c.1551+1G>C

Variant 2 ClinVarID: 554983

Variant 2 CAid: CA401367167

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient19: Male

CasePresentingHPOs: HP:0004887, HP:0011471, HP:0002546, HP:0001371

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, tracheostomy, able to sit independently, heart normalization, moderate periventricular white matter abnormalities (hypomyelination)

CaseNotHPOs: HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 10 days, diagnosis and ERT at 3 years

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1802C>G (p.Ser601Trp)

ClinVar: 501793, https://www.ncbi.nlm.nih.gov/clinvar/variation/501793/

gnomAD: n/a

Variant2: NM_000152.3:c.2800-1G>C

CAID: CA401327625, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401327625

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

PMID: 31256280

Gene: GAA

Disease: Pompe Disease

Inheritance: Autosomal Recessive

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

Case2: Male, Danish, 39 years report, 20 years onset

CasePresentingHPOs: HP:0008956 (Thigh muscle atrophy)

HPOsFreeText: 6-min walk test achieved 441 m, MRC score is 4/5 (thigh/calf), Forced vital capacity sitting/supine is 4.1/3.7 (L)

NotHPOsFreetext: Not on ERT

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.2331+2T>G

CAID: CA401324960 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2331%2B2T%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

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

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

CaseNotHPOs: HP:0008956 (Thigh muscle atrophy)

GroupGenotypingMethod: Mutation Analysis on the GAA Gene

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

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

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

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

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

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 5, Gender N/A, Onset at 5-6 months. Death at 1.5 years of age, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165, HP:0001270, HP:0001252, HP:0001714, HP:0002090

(Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval, Motor delay, Muscular hypotonia, Ventricular hypertrophy, Pneumonia )

CaseHPOFreeText: Death from heart failure and pneumonia

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0% of normal control value.

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

Variant 1: NM_000152.5(GAA):c.1538A>G (p.Asp513Gly)

ClinVar: 638014

CAID: CA401367134

gnomAD: N/A

ParentalGenotype: Both parents carried the .1538A>G (p.Asp513Gly) variant in the GAA gene. There was no parental consanguinity

PreviouslyPublished: N/A

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

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

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

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

CaseNotHPOs:

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

CasePreviousTesting:

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

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

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

ClinVar: 371302

CAID: 16041880

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

ClinVar:279811

CAID: 8815429

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

Case#: Patient 6, Female, 5.5 months old at diagnosis, Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001252, HP:0001638

(Muscular hypotonia, Cardiomyopathy)

CaseHPOFreeText:

Previous to ERT, patient was invasively ventilated, and had . Also Aspiration and penetration with feeding and started on NG tube feeds at baseline

Current patient has marked axial and peripheral hypotonia, G-tube feeds and requires BiPAP at night. Patient has near-complete lower extremity immobility

CaseNotHPOs: N/A

CaseNotHPOFreeText: Antigravity movement in arms

CasePreviousTesting: N/A

Variant: NM_000152.5(GAA):c.525_526del (p.Asn177fs) Please double check

ClinVar: 189057

CAID: CA274328

gnomAD: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient7: male, 40yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 25.1 / 22.9 / 22.9, WGMS = 3 / 3 / 3

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Variant2: NM_000152.3:c.1291_1299del

CAID: CA658795248, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795248

gnomAD: n/a

PatientF1P4: Male, birth onset, prenatal diagnosis, Caucasian

HPOsFreeText: IOPD was confirmed with decreased acid GAA on a lymphocyte assay (6 nmol/hr/mg, control 36 nmol/hr/mg) and on a foreskin fibroblast sample,

CaseAddInfo: First cousin twice removed of F1P1, Mother carries both c.1880C>T and VUS c.1642G>T mutations in cis

Case#: Patient 3, male, 21 year old, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: No family history of muscle disease

CasePresentingHPOs: HP:0003236, HP:0100284

(Elevated serum creatine kinase, EMG: myotonic discharges

CaseHPOFreeText: Mild weakness (4/5) of iliopsoas muscles

Myotonic discharges in the lumbar paraspinal muscles

Elevated aspartate aminotransferase of 172 I/U ( Normal range 19–55 I/U)

Elevated alanine aminotransferase of 203 I/U (Normal range 19–72 I/U)

Serum CK was elevated at 1,373 U/L (normal range 70–185 U/L)

CaseNotHPOs:

CaseNotHPOFreeText: Normal alkaline phosphatase and γ-glutamyl transpeptidase levels.

Liver ultrasound and biopsy at an outside facility were normal

CasePreviousTesting: GAA level was 1.4 pmol/punch/h (normal range 10–49 pmol/punch/h)

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

ClinVar: 4027

CAID: CA116606

gnomAD: Hughest population MAF= 0.005541 (Ashkenazi Jewish)

Variant 2: NM_000152.5(GAA):c.877G>A (p.Gly293Arg)

ClinVar: 4036

CAID: CA116622

gnomAD: Highest population MAF= 0.00005704 (Latinos)

ParentalGenotype:N/A

PreviouslyPublished:N/A

Case31: 2 mo (at biopsy), Indian

Case 31 (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 1.9 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.257C>T (p.Pro86Leu)

ClinVar: 553773

CAID: CA3847150

gnomAD: 0.00009799 (South Asian)

CaseAddInfo: mut- type, homozygous mutations. documented consanguinity.

Case30: 6 wks (at biopsy), Pakistani

Case 30 (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.55dupG (p.Val19Glyfs)

ClinVar: 222906

CAID: CA10575888

gnomAD: n/a

CaseAddInfo: mut0 type, homozygous mutations. novel variant.

Case28: 1 y 1 mo (at biopsy), European

Case 28 (Level 2)

CasePreviousTesting: same as group. found 1.1 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1181dupT (p.Leu394Phefs)

ClinVar: 222930

CAID: CA10575868

gnomAD: n/a

Variant2: NM_000255.3:c.1975C>T (p.Gln659Ter)

ClinVar: 222939

CAID: CA10575859

gnomAD: n/a

CaseAddInfo: mut0 type. both novel mutations. heterozygous mutations, unknown cis or trans.

Case27: no age or ethnicity recorded

Case 27 (Level 2)

CasePreviousTesting: same as group. found 0.4 nmol/mg protein/18 h propionate incorporation, 0.4 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1061delCinsGGA (p.Ser354TrpfsTer20)

ClinVar: n/a

CAID: CA913187308

gnomAD: n/a

Variant2: NM_000255.3:c.1065_1068dupATGG (p.Ser357MetfsTer5)

ClinVar: 280817

CAID: CA10602989

gnomAD: n/a

CaseAddInfo: mut0 type. both novel mutations. heterozygous mutations. Examination of NGS reads determined mutations are in trans

Case26: 7 y (at biopsy), Hispanic

Case 26 (Level 2)

CasePreviousTesting: same as group. found 4.5 nmol/mg protein/18 h propionate incorporation, 7.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.970G>A (p.Ala324Thr)

ClinVar: 550893

CAID: CA364400785

gnomAD: 0.0001632 (Other)

Variant2: NM_000255.3:c.1846C>T (p.Arg616Cys)

ClinVar: 551499

CAID: CA3846722

gnomAD: 0.00008688 (Latino)

CaseAddInfo: mut- type, heterozygous mutations, unknown cis or trans. Protein change in paper (p.P649L) is different than protein change indicated by clin var and CAID (p.Arg616Cys).

Case29: 3 mo (at biopsy), Chinese

Case 29 (Level 2)

CasePreviousTesting: same as group. found 0.3 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1280G>A (p.Gly427Asp)

ClinVar: 218990

CAID: CA347873

gnomAD: 0.0004011 (East Asian)

Variant2: Exon 13 deletion

ClinVar: n/a

CAID: n/a

gnomAD: n/a

CaseAddInfo: Variant 2 is novel. Heterozygous mutations in MUT, unknown cis or trans. Additional variant found in TCN2 gene (NM_000355.3:c.509G>A, ClinVar: 341197, CAID: CA10184685, gnomAD: 0.007469 (East Asian)). heterozygous Exon 13 deletion confirmed by microarray-based comparative genomic hybridization.

Case25: 25 y (at biopsy), White

Case 25 (Level 2)

CasePreviousTesting: same as group. found 1.3 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.935G>T (p.Gly312Val)

ClinVar: 218988

CAID: CA347874

gnomAD: n/a

Variant2: NM_000255.3:c.1909G>A (p.Gly637Arg)

ClinVar: n/a

CAID: CA3846712

gnomAD: [0.000008798] (http://insert-your-link-here.com)(European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans.

Case24: no age or ethnicity recorded

Case 24 (Level 2)

CasePreviousTesting: same as group. found 0.4 nmol/mg protein/18 h propionate incorporation, 0.4 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.795_796insT or NM_000255.3:c.795dupT (p.Met266TyrfsTer7)

ClinVar: n/a

CAID: CA913187322

gnomAD: n/a

Variant2: NM_000255.3:c.1207C>T (p.Arg403Ter)

ClinVar: 167310

CAID: CA234287

gnomAD: 0.0001602 (African)

CaseAddInfo: Variant 1 is novel. Mut0 type, heterozygous mutations, unknown cis or trans.

Case23: 3 mo (at biopsy), French Canadian

Case 23 (Level 2)

CasePreviousTesting: same as group. found 1.4 nmol/mg protein/18 h propionate incorporation, 1.3 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.753+3A>G

ClinVar: n/a

CAID: CA3847056

gnomAD: 0.000008890 (European non-Finnish)

Variant2: NM_000255.3:c.1332+1delG

ClinVar: 554656

CAID: CA3846920

gnomAD: 0.000008828 (European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans. Variant 1 is novel.

Case22: 28 mo (at biopsy), Korean

Case 22 (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 0.8 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

Variant2: NM_000255.3:c.1481T>A (p.Leu494Ter)

ClinVar: 551275

CAID: CA3846864

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans

Case21: 2 mo (at biopsy), White

Case 21 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

Variant2: NM_000255.3:c.1287C>G (p.Tyr429Ter)

ClinVar: 554278

CAID: CA364398724

gnomAD: 0.00006483 (European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans.

Case20: 5 days (at biopsy), White

Case 20 (Level 2)

CasePreviousTesting: same as group. found 2.1 nmol/mg protein/18 h propionate incorporation, 1.9 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

Variant2: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans.

Patient2: Female, 5.5yo

CasePresentingHPOs: HP:0002572, HP:0001259, HP:0003648, HP:0002919 (episodic vomiting, coma, lacticaciduria, ketonuria)

HPOsFreeText: chronic intermittent IVA, treated with a vegetarian diet and L-carnitine supplements, abnormal excretion of isovalerate metabolites, elevation of isovaleryl glycine in urine, C5-carnitine = 16 µmol/l, birth weight = 2kg, hospitalized at 2yo for vomiting and acidosis. At physical exam at 5.5yo, weight = 18kg, height = 103cm, IQ = 92, and unremarkable systemic examination

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 4mo at onset, 13mo at diagnosis via clinical presentation, consanguineous family, full-term delivery via Caesarean section due to failure of propagation

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.1207T>A

CAID: CA391724509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724509

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient3: Female, 22yo

CasePresentingHPOs: HP:0001249 (intellectual disability)

HPOsFreeText: Blood C5-carnitine (μM) = 14.27, under a protein restricted diet with carnitine and glycine supplementation

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3yo after improper treatment

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.1007G>A (p.Cys309Tyr) listed in paper as (p.Cys307Tyr)

CAID: CA391722967, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391722967

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient5-2 Female, 1yo, sibling to patient 5-1

CasePresentingHPOs:

HPOsFreeText: Blood C5-carnitine (μM) = 13.47, under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2mo and asymptomatic at diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.347C>T (p.Ser89Phe) listed in paper as (p.Ser87Phe)

CAID: CA391716394, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716394

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

CaseOS-127_II-1: Male, Birth onset, Germany

CasePresentingHPOs: HP:0001992, HP:0410145 (Organic aciduria, Decreased biotinidase activity)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous and healthy; Proband is confirmed homozygous via parental testing

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; Biotinidase deficiency treated via 5 mg biotin/d

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

Case6: Male, White

CasePresentingHPOs: HP:0012072, HP:0002194, HP:0002788, HP:0001256, HP:0000722, HP:0000750, HP:0002360, HP:0005487, HP:0002057, HP:0000664, HP:0000286, HP:0000494, HP:0000368, HP:0000322, HP:0009778, HP:0004209 (Aciduria, Delayed gross motor development, Recurrent upper respiratory tract infections, Mild intellectual disability, Obsessive-compulsive behavior, Delayed speech and language development, Sleep disturbance, Prominent metopic ridge, Prominent glabella, Synophrys, Epicanthus, Downslanted palpebral fissures, Low-set posteriorly rotated ears, Short philtrum, Short thumb, Clinodactyly of the 5th finger)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous

CasePreviousTesting: Extensive metabolic screening revealed elevated urine AAA (618 mmol/mol creatinine; ref <49) and KAA (348 mmol/mol creatinine; ref not detected) as well as plasma AAA (53 umol/L; ref <12)

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant1: NM_018706.6:c.2185G>A (p.Arg455Gln)

CAID: CA5407838 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407838

gnomAD: 0.0002538, https://gnomad.broadinstitute.org/variant/10-12139688-G-A

Variant2: NM_018706.6:c.1159+5G>A

CAID: CA5407761 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407761

gnomAD: 0.0001170, https://gnomad.broadinstitute.org/variant/10-12133688-G-A

Case10: Male, Mixed, 6 yrs died

CasePresentingHPOs: HP:0002240, HP:0006579, HP:0003560, HP:0001263, HP:0002376 (Hepatomegaly, Prolonged neonatal jaundice, Muscular dystrophy, Global developmental delay, Developmental regression)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; Niemann-Pick type C disease was diagnosed via bone marrow investigations; Metabolic screening suggested a defect in lysine metabolism with urine values of AAA and KAA increasing following a lysine challenge (200 mg/kg p.o.)

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant: NM_018706.6:c.700_701delinsGG (p.Leu234Gly)

CAID: CA915940679 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA915940679

gnomAD: Not in gnomAD

CaseAD: Male, 5 yrs onset

CasePresentingHPOs: HP:0000750, HP:0002572, HP:0012537, HP:0001944, HP:0001649, HP:0002789, HP:0001252, HP:0001942, HP:0001987, HP:0002919, HP:0012120 (Delayed speech and language development, Episodic vomiting, Food intolerance, Dehydration, Tachycardia, Tachypnea, Muscular hypotonia, Metabolic acidosis, Hyperammonemia, Ketonuria, Methylmalonic aciduria)

HPOsFreeText: Frequent catabolism episodes with vomiting were noticed without decompensation

CaseNotHPOs: HP:0001270, HP:0001919, HP:0011015 (Motor delay, Acute kidney injury, Abnormal blood glucose concentration)

NotHPOsFreeText: Propionyl-CoA carboxylase activity was within normal ranges in fibroblasts

CaseAddInfo: Parents are non-consanguineous with no family history, Dietary restriction and supplementation showed amelioration of symptoms

CasePreviousTesting: Normal ECG and MRI results; Metabolic acidosis (pH = 7.08, bicarbonates = 7.3 mmol/L, normal lactic acid, PCO2 = 25 mmHg) and hyperammmoniemia (100 µmol/L) present; Large increase in plasmatic propionylcarnitine (17.5 µmol/L; N < 0.75), undetectable methylmalonylcarnitine, and high urinary excretion of 3-hydroxypropionate and methylcitrate

CaseGenotypingMethod: Next-generation sequencing in the proband revealed a homozygous nonsense founder variant in the MCEE gene.

Variant: NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)

ClinVar: 2343, http://www.ncbi.nlm.nih.gov/clinvar/variation/2343

gnomAD: 0.0004884, https://gnomad.broadinstitute.org/variant/2-71351575-G-A

Case12(Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group __

Variant1: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

Variant2: NM_015506.2(MMACHC):c.481C > T (p.Arg161Ter)

ClinVar: 95703

CAID: CA223189

gnomAD: 0.0001241 (African)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) not a carrier

Case 7 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

Variant2: NM_015506.2(MMACHC):c.445_446delTG (p.Cys149Hisfs*32)

ClinVar: 203834

CAID: CA312741

gnomAD: 0.00008509 (Latino)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for both variants