Case39

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

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

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.525delT (p.Glu176Argfs*45)

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

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

CaseAddInfo: Infantile Onset Pompe Disease, 1 more patient has the same genotype

Patient5: female, 53yo, adult onset

CasePresentingHPOs:

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

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

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

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

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

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

DiseaseAssertion:Pompe disease

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

FamilyInfo: No family history of muscle disease

CasePresentingHPOs: HP:0003701, HP:0100284

(Proximal muscle weakness, EMG myotonic discharges)

CaseHPOFreeText: Denervation atrophy from a muscle biopsy

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

Found with two mutations in the GAA gene

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

ClinVar: 4027

CAID: CA116606

gnomAD: Highest population MAF= 0.005541 (Ashkenazi Jewish)

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

ClinVar: 4033

CAID: CA220406

gnomAD: N/A

ParentalGenotype:N/A

Previously Published: N/A

Case22: Male, 0.5 yr onset, 1 yr diagnosis, 1.3 yr report

HPOsFreeText: Wheelchair used at 4 yr, Died of respiratory failure at 10 yr, FVC z-score sitting -4.77 (45% pred) at 9 yr, 586 CK U/l, Deficient GAA activity (nmol/h/mg)^h from cultured fibroblasts

Case#: Patient 4, male, diagnosed 2015 (not given age of diagnosis), age 42 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.525del

Variant 2 ClinVarID: 4033

Variant 2 CAid: CA220406

ParentalGenotype: Not provided

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

Patient3: Male, Caucasian, 11yo

CasePresentingHPOs:

HPOsFreeText: IOPD, negative rhGAA IgG antibody titer, CRIM positive

CaseNotHPOs:

NotHPOsFreeText: no infusion associated reactions

CaseAddInfo: diagnosed at birth, 15days old at ERT start

CasePMIDs:

CasePreviousTesting: same as group

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

Variant2: NM_000152.5(GAA):c.1642G>T (p.Val548Phe)

ClinVar: 5973381, https://www.ncbi.nlm.nih.gov/clinvar/variation/597381/

gnomAD: n/a

Variant3: NM_000152.5(GAA):c.1880C>T (p.Ser627Phe)

ClinVar: 597382, https://www.ncbi.nlm.nih.gov/clinvar/variation/597382/

gnomAD: n/a