Case: IP #1

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11.4; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.421G>A p.Asp141Asn

HGVS:

ClinVarID: 100338

CAID:

gnomAD: absent

Case: IP #3 (also in row 1 splice variants table 6)

DiseaseAssertion: Type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 49; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1110-6_1110-5insC

HGVS: NM_000552.5:c.1110-6dup p.?

ClinVarID: 507028

CAID:

gnomAD: absent

Case: IP #4

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 117; VWF:Ac [IU/dL] = 52; FVIII:C [IU/dL] = 104

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1309_1326del p.Asp437_Arg442del

HGVS:

ClinVarID: 100179

CAID:

gnomAD: 0.000001239 (2 in 1614154) no homozygotes https://gnomad.broadinstitute.org/variant/12-6064351-AGCGGGTGCACACAGCGTC-A?dataset=gnomad_r4

Case: IP #15

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 41; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 82

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3390C>T p.Cys1130Cys

HGVS:

ClinVarID: 627186

CAID:

gnomAD: 0.000006021 (3 in 498246) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022888-G-A?dataset=gnomad_r4

Case: IP #39

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 110; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 103

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4645G>A p.Glu1549Lys

HGVS:

ClinVarID: 100379

CAID:

gnomAD: absent

Case: IP #13 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 47; VWF:Ac [IU/dL] = 46; FVIII:C [IU/dL] = 86; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #57

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 53; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: IP #1 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 37; VWF:Ac [IU/dL] = 36; FVIII:C [IU/dL] = 46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.-411T>C

HGVS:

ClinVarID: not found

CAID: not found

gnomAD: absent

**MultipleGeneVariants:

Gene: VWF

Variant: c.+167G>T

Gene: VWF

Variant: c.2278C>T p.Arg760Cys

ClinVarID: 100208

gnomAD: 0.000006196 (10 in 1614050) no homozygotes https://gnomad.broadinstitute.org/variant/12-6046726-G-A?dataset=gnomad_r4

Case: IP #24 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: 0.000003098 (5 in 1613796) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019298-G-A?dataset=gnomad_r4

Case: IP #2 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 18

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2625C>T p.Tyr875=

HGVS:

ClinVarID: 439330

CAID:

gnomAD: 0.000003717 (6 in 1614106) no homozygotes https://gnomad.broadinstitute.org/variant/12-6034748-G-A?dataset=gnomad_r4

Case: P13, Chinese, male, 8yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 5; VWF:Ag (%) = 21.6, VWF:RCo (%) = 9.4, FVIII:C (%) = 53.2, VWF:CB (%) = 5.7, VWFpp (%) = 56.1, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P65, Chinese, female, 24yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 55.7, VWF:RCo (%) = 51.2, FVIII:C (%) = 72.7, VWF:CB (%) = 57.1, VWFpp (%) = 61.7, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4499C>T (p.Ala1500Val)

HGVS: NM_000552.4(VWF):c.4499C>T (p.Ala1500Val)

ClinVarID: 439339; https://www.ncbi.nlm.nih.gov/clinvar/variation/439339/

CAID: NA

gnomAD: MAF = 0.003511 (70/19938 alleles) in the East Asain population; https://gnomad.broadinstitute.org/variant/12-6128085-G-A?dataset=gnomad_r2_1

Case: P4, Chinese, male, 35yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 22.6, VWF:RCo (%) = 5.0, FVIII:C (%) = 36.6, VWF:CB (%) = 25.4, VWFpp (%) = 43.0, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.9, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P79, Chinese, female, 24yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 9; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.7, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 11.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1093C>T (p.Arg365Ter)

HGVS: NM_000552.4(VWF):c.1093C>T (p.Arg365Ter)

ClinVarID: 100172; https://www.ncbi.nlm.nih.gov/clinvar/variation/100172/

CAID: NA

gnomAD: absent

Variant 2: c.4975C>T (p.Arg1659Ter)

HGVS: NM_000552.4(VWF):c.4975C>T (p.Arg1659Ter)

ClinVarID: 297; https://www.ncbi.nlm.nih.gov/clinvar/variation/297/

CAID: NA

gnomAD: MAF = 0.0004007 (10/24958 alleles) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6127609-G-A?dataset=gnomad_r2_1

Case: P45, Chinese, female, 8yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 23.5, VWF:RCo (%) = 6.5, FVIII:C (%) = 40.0, VWF:CB (%) = 15.2, VWFpp (%) = 44.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.6, VWFpp/VWF:Ag = 1.9, FVIII:C/VWF:Ag = 1.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4628C>T (p.Ser1543Phe)

HGVS: NM_000552.4(VWF):c.4628C>T (p.Ser1543Phe)

ClinVarID: 100376; https://www.ncbi.nlm.nih.gov/clinvar/variation/100376/

CAID: NA

gnomAD: absent

Case: P52, Chinese, female, 55yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 19.1, VWF:RCo (%) = 3.1, FVIII:C (%) = 35.8, VWF:CB (%) = 22.7, VWFpp (%) = 50.3, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 1.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>A (p.Arg1374Ser)

HGVS: NM_000552.4(VWF):c.4120C>A (p.Arg1374Ser)

ClinVarID: 100328; https://www.ncbi.nlm.nih.gov/clinvar/variation/100328/

CAID: NA

gnomAD: absent

Case: Tjenberg_2006_Patient_III-5, female, blood type O

DiseaseAssertion: VWD2A

FamilyInfo: The phenotypes of the 3 affected family members and 3 unaffected family members are documented in Table I, while the pedigree and genotypes are shown in Figure IA.

ParentalGenotype(s): The parental genotype is unknown, but the affected daughter of the proband has inherited the variant.

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0030129 (Impaired ristocetin cofactor assay activity), HP:0000978 (Bruising susceptibility), HP:0004406 (Spontaneous, recurrent epistaxis), HP:0000132 (Menorrhagia), HP:0040225 (Decrease in high molecular weight von Willebrand factor Multimers)

CaseHPOFreeText: bleeding time > 15 minutes, bleeding score of 10, aberrant odd-numbered VWF multimers observed between the normal multimers

CaseNOTHPOs: HP:0030976 (Abnormal factor VIII activity)

CaseNOTHPOFreeText: Normal VWF antigen level

CasePreviousTesting: Because of the detailed clinical phenotype, genotyping was limited to the VWF locus alone.

GenotypingMethod: Genotyping consisted of PCR amplification and Sanger sequencing of exons 51 and 52 of the VWF gene.

PreviouslyPublished: N/A

Gene: VWF

Variant: NM_000552.5(VWF):c.8318G>C (p.Cys2773Ser)

ClinVarID: 100503

gnomAD: This variant is absent from gnomAD v2.1.1 and v3.1.2.

Case: 2M-3

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.50; AcuStar CB/Ag = 0.63; ELISA CB/Ag = 0.94

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2M-5

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.37; AcuStar CB/Ag = 0.41; ELISA CB/Ag = 0.62

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: Male, described as "a small child"; exact age not stated. Born at 26 weeks' gestation (extreme prematurity) by C-section for suspected placental abruption/preterm labor; perinatal course complicated by mild bronchopulmonary dysplasia and retinopathy of prematurity. DiseaseAssertion: Type 2B VWD, based on reduced VWF:RCo/Ag ratio (<0.7), absence of high- and intermediate-molecular-weight VWF multimers, and increased binding of patient VWF to formalin-fixed normal platelets at low ristocetin concentration (the gain-of-function assay that distinguishes Type 2B from Type 2A or platelet-type VWD). FamilyInfo: NA — no relatives' bleeding history or genotype reported for this patient. ParentalGenotype(s): NA (not tested/not reported) CasePresentingHPOs: HP:0001873 (Thrombocytopenia; platelet counts ranged 5,000-30,000/µL), HP:0012147 (Reduced quantity of VWF; VWF:Ag 54 then 26 IU/dL on repeat testing, nv 45-170 / 50-240), HP:0030129 (Impaired VWF:RCo; 24 then <10 IU/dL, nv >50 / 54-279), HP:0030132 (Absence of large VWF multimers — both high- and intermediate-weight multimers absent on electrophoresis) CaseHPOFreeText: Numerous purpura and petechiae on face, limbs, and trunk; easy bruising and bleeding from oral mucous membranes (no matching HPO code in the approved list); FVIII activity low-normal to reduced (63 then 27 IU/dL, nv 60-200 / 60-195); circulating platelet agglutinates seen on peripheral blood smear; bone marrow aspirate showed large platelet clumps and megakaryocyte nuclei surrounded by halos of clumped platelets — the paper's key finding, suggesting platelet agglutination occurs within the bone marrow itself, not only peripherally; increased binding of patient VWF to formalin-fixed normal platelets specifically at low ristocetin concentration (gain-of-function finding diagnostic for Type 2B, distinct from the reduced standard-dose VWF:RCo activity above). CaseNOTHPOs: NA CaseNOTHPOFreeText: No hepatosplenomegaly, no orthopedic abnormalities on exam; no schistocytes noted on peripheral smear (argues against a microangiopathic process). CasePreviousTesting: Targeted sequencing of VWF exon 28 specifically, clinically directed given the suspected Type 2B phenotype (Type 2B-causing mutations characteristically cluster in exon 28). Not genome-wide, not full VWF gene sequencing. GenotypingMethod: Gene sequencing of VWF exon 28 (specific sequencing platform not stated in the paper). PreviouslyPublished: PMID 15231945 (Christensen RD, Sola MC, Rimsza LM, et al. "Pseudothrombocytopenia in a preterm neonate." Pediatrics. 2004;114:273-275) — same patient, reported before the VWD diagnosis was established. Gene: VWF Variant: Heterozygous missense c.3923G>C, exon 28, p.Arg1308Pro. Same mutation previously reported in a different, unrelated family (Nurden et al. 2006, Blood, PMID 16720832) with abnormal megakaryocyte platelet release in CD34+ cell culture; this report extends that finding by showing the abnormality occurs in vivo in the bone marrow in a patient with this genotype. HGVS: NM_000552.5:c.3923G>C (p.Arg1308Pro). Paper states this directly ("G to C mutation at base 3923... arginine 1308 with proline"); also reports the older mature-protein numbering, R545P (offset of 763 residues, consistent with the length of the VWF signal peptide + propeptide). I independently corroborated the codon position: nt 3922-3924 = codon 1308, matching a real, independently confirmed ClinVar entry at the same codon for a different substitution (c.3922C>T, p.Arg1308Cys). ClinVarID: 100304 (VCV000100304.2) CAID: NA gnomAD: NA

Case: Row 13 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.5; VWFpp/VWF:Ag = 1.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1955G>T C652F

HGVS: VWF:c.1955G>T (p.Cys652Phe)

ClinVarID: 1695348

CAID:

gnomAD: absent

Case: Row 22 in Supplemental Table 1.

DiseaseAssertion: VWD type 1

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.6; VWFpp/VWF:Ag = 1.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2878C>T R960W

HGVS: VWF:c.2878C>T p.Arg960Trp

ClinVarID: 1033091

CAID:

gnomAD: 0.0001295 (209 in 1614054) no homozygotes https://gnomad.broadinstitute.org/variant/12-6029431-G-A?dataset=gnomad_r4

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.3133C>T (p.Arg1045Cys)

ClinVar: 177753, https://www.ncbi.nlm.nih.gov/clinvar/variation/177753/

gnomAD: 0.00002828, https://gnomad.broadinstitute.org/variant/14-23891501-G-A

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.2783A>T (p.Asp928Val)

ClinVar: 181379, https://www.ncbi.nlm.nih.gov/clinvar/variation/181379/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.2080C>T (p.Arg694Cys)

ClinVar: 177627, https://www.ncbi.nlm.nih.gov/clinvar/variation/177627/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23895255-G-A

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.5786C>T (p.Thr1929Met)

ClinVar: 181397, https://www.ncbi.nlm.nih.gov/clinvar/variation/181397/

gnomAD: n/a

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.2539A>G (p.Lys847Glu)

ClinVar: 177757, https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

gnomAD: n/a

CaseV-4: 14 year old male, Chinese

DiseaseAssertion: Laing distal myopathy

FamilyInfo: five-generation Chinese family with suspected limb-girdle muscle dystrophy

CasePresentingHPOs: HP:0002650, HP:0003691, HP:0008981

"Scoliosis, Scapular winging, Calf muscle hypertrophy

CaseHPOFreeText: Toe dorsiflexion difficulty, foot drop, leg weakness, limb girdle weakness,

CaseNotHPOFreeText: Finger extensor weakness, Neck flexion weakness

CasePreviousTesting: sanger sequencing HSPA6

GenotypingMethod: whole exome sequencing, sanger sequencing

Variant: NM_000257.4:c.4850_4852del

ClinVar: 190401

CAID: CA015411

gnomAD: not found

DiseaseAssertion: Dilated Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, and VCL were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 74 DCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in two DCM probands and relatives

Variant: NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys)

ClinVarID: 181278 https://www.ncbi.nlm.nih.gov/clinvar/variation/181278/

gnomAD: Not in gnomAD

Supplementary Data Table S3

Case: 344

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2348G>A (p.Arg783His)

ClinVar: 180437 https://www.ncbi.nlm.nih.gov/clinvar/variation/180437/

gnomAD: 0.00004005, https://gnomad.broadinstitute.org/variant/14-23894566-C-T

MultipleGeneVariants:

(1) ABCC9 Variant

Variant: NM_005691.3(ABCC9):c.2200G>A (p.Val734Ile)

ClinVar: 35627 https://www.ncbi.nlm.nih.gov/clinvar/variation/35627/

gnomAD: 0.01123, https://gnomad.broadinstitute.org/variant/12-22017410-C-T

Supplementary Data Table S3

Case: 111

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.1193G>A (p.Gly398Glu)

ClinVar: 180434 https://www.ncbi.nlm.nih.gov/clinvar/variation/180434/

gnomAD: 0.0001946, https://gnomad.broadinstitute.org/variant/14-23898502-C-T

MultipleGeneVariants:

(1) DSP Variant

Variant: NM_004415.4(DSP):c.5498A>T (p.Glu1833Val)

ClinVar: 44929 https://www.ncbi.nlm.nih.gov/clinvar/variation/44929/

gnomAD: 0.02491, https://gnomad.broadinstitute.org/variant/6-7582993-A-T

(2) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

(3) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

Supplementary Data Table S3

Case: 278

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2348G>A (p.Arg783His)

ClinVar: 180437 https://www.ncbi.nlm.nih.gov/clinvar/variation/180437/

gnomAD: 0.00004005, https://gnomad.broadinstitute.org/variant/14-23894566-C-T

MultipleGeneVariants:

(1) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Data: Online Table 2b

Case 6:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant 1: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607, https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 2b

Case 5:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant 1: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607, https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.2704G>A (p.Glu902Lys)

ClinVar: 228905, https://www.ncbi.nlm.nih.gov/clinvar/variation/228905/

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.2678C>T (p.Ala893Val)

ClinVar: 177763, https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/

gnomAD: n/a

Case1: Female, 33 yrs report

DiseaseAssertion: MYH7 Gene-Related Skeletal Myopathy

FamilyInfo: Uneventful family history

CasePresentingHPOs: HP:0002650, HP:0001324, HP:0001263, HP:0001252, HP:0006794, HP:0002652, HP:0002751, HP:0002094, HP:0003121, HP:0003044, HP:0006471, HP:0003273, HP:0008112 (Scoliosis, Muscle weakness, Global developmental delay, Muscular hypotonia, Loss of ability to walk in first decade, Skeletal dysplasia, Kyphoscoliosis, Dyspnea, Limb joint contracture, Shoulder flexion contracture, Fixed elbow flexion, Hip contracture, Plantar flexion contractures)

CaseHPOFreeText: EMG: short duration, small amplitude motor unit action potential (MUAP), and early recruitment patterns were observed in the involved proximal muscles

CaseNotHPOs: HP:0001239, HP:0012785, HP:0002127, HP:0100543 (Wrist flexion contracture, Flexion contracture of finger, Abnormal upper motor neuron morphology, Cognitive impairment)

CaseNotHPOFreeText: No significant abnormal findings during the perinatal period and at the time of birth

CasePreviousTesting: SMN 1del/dup test was performed and no specific findings were observed, Physical exam, serologic test, and neurophysiologic test, including nerve conduction study (NCS) and electromyogram (EMG), were performed, On the manual muscle test (MMT) she received a grade of 4 for wrist flexor, extensor muscle, finger flexor, and extensor muscle, and a grade of 1 for all other upper and lower limb muscles, Cobb angle was 126° at the time of measurement, NGS using a targeted gene sequencing panel analyzing 293 genes performed using 2 x 150 bp in the paired-end mode of MiSeq platform from Illumina

CaseGenotypingMethod: Chromosomal microarray was performed with no abnormal findings. A NGS study was then performed on the proband using a targeted gene sequencing panel for neuromuscular diseases. Genomic DNA was extracted and captured, with massively parallel sequencing and subsequent reading and annotating/filtering of any located variants.

Variant: NM_000257.4:c.1495_1497delGAG (p.Glu500del)

ClinVar: 525034

gnomAD: Not in gnomAD

Case#: 12th case, male, 35 years

DiseaseAssertion: SHCM

FamilyInfo: No

CasePresentingHPOs: Mycardial fibrosis (HP:0001685)

CaseHPOFreeText: 494 g heart, IVST to LVWT ratio 1.35, IVST 2.3 cm, LVWT 1.7 cm, hypertrophy of myocardial fibers, stenosis in lumens,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no pathological changes found in major organs besides heart

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, 2D and Doppler echocardiography, histological examinations, genomic DNA extraction, DNA cloning, sequence analysis

Variant: NM_000257.4(MYH7):c.1402T>C (p.Phe468Leu)

ClinVar: 177821 https://www.ncbi.nlm.nih.gov/clinvar/variation/177821/

CAID: N/A

gnomAD: absent

CaseMYH7-8: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.4075C>T (p.Arg1359Cys)

ClinVar: 178082 https://www.ncbi.nlm.nih.gov/clinvar/variation/178082/

gnomAD: European (Non-Finnish) 8.793e-6, Overall 7.954e-6 https://gnomad.broadinstitute.org/variant/14-23887513-G-A

CaseMYH7-22: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.2333A>T (p.Asp778Val)

ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/

gnomAD: Not in gnomAD

CaseIII-1: 53 years old at time of report

DiseaseAssertion: Laing distal myopathy

FamilyInfo: Mutation in the MYH7 gene was cosegregated within the family members. In this family, the mutation segregated to the three affecteds, but not to any of the six unaffecteds

CasePresentingHPOs: HP:0008997, HP:0008994, HP:0009053, HP:0008959, HP:0100595

"Proximal muscle weakness in upper limbs, Proximal muscle weakness in lower limbs, Distal lower limb muscle weakness, Distal upper limb muscle weakness, camptocormia"

CaseHPOFreeText: hanging big toes and early involving neck flexors at the age of 8 years, atrophies in both sternocleidomastoid muscles, posture showed asymmetry of muscle atrophy, shoulder elevation

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Level of serum creatine kinase was 534 IU/L (normal range < 185 IU/L). Echocardiogram and serum cardiac enzyme activity were normal. Needle electromyography showed generalized myopathic patterns, while nerve conduction studies were normal. "several functionally significant variants were identified from myopathy-related genes"

GenotypingMethod: whole exome sequencing, capillary DNA sequencing, and in silico analysis

Variant: NM_000257.3:c.4315G>C

ClinVar: 190404

CAID: CA347256

gnomAD: not found

Case: Patient 13, female, 59yo, symptom onset in adulthood

CasePresentingHPOs: HP:0003701, HP:0003306, HP:0003458 (proximal muscle weakness, rigid spine, EMG: myopathic abnormalities)

HPOsFreeText: normal CK levels, cores present on muscle biopsy

CaseNotHPOs: no respiratory or cardiac involvement

FamilyInfo: family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4315G>C (p.Ala1439Pro)

ClinVar: 190404, https://www.ncbi.nlm.nih.gov/clinvar/variation/190404/

gnomAD: absent

Case: Patient 8, male, 35yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0002460, HP:0002650, HP:0003458 (foot drop, axial muscle weakness, distal muscle weakness, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: CK = 720U/l, neurogenic EMG, cores present on muscle biopsy

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant 1: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Variant 2: NM_000257.4(MYH7):c.4855G>A(p.Glu1619Lys)

ClinVar: 181268, https://www.ncbi.nlm.nih.gov/clinvar/variation/181268/

gnomAD: absent

Table 5

Case LO1: Italian

DiseaseAssertion: HCM (late-onset)

FamilyInfo: positive family history

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography

CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing

Variant: NM_000257.3(MYH7):c.3133C>T (p.Arg1045Cys)

ClinVar: 177753, https://www.ncbi.nlm.nih.gov/clinvar/variation/177753/

gnomAD: 0.00002828, https://gnomad.broadinstitute.org/variant/14-23891501-G-A

Supplementary Data: Table 2

Case A: proband, female

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, LMNA)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case L:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case N:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, MYBPC3)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case H: proband, Female

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case F: proband, Female

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case J: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case D: proband, female

DiseaseAssertion: Hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) DSC2 Variant:

Variant: NM_004949.4(DSC2):c.2194T>G (p.Leu732Val)

ClinVar: 36005, https://www.ncbi.nlm.nih.gov/clinvar/variation/36005/

gnomAD: 0.001181, https://gnomad.broadinstitute.org/variant/18-28650748-A-C

(2) DSG2 Variant:

Variant: NM_001943.4(DSG2):c.1174G>A (p.Val392Ile)

ClinVar: 36009, https://www.ncbi.nlm.nih.gov/clinvar/variation/36009/

gnomAD: 0.002137, https://gnomad.broadinstitute.org/variant/18-29111109-G-A

(3) DSP Variant:

Variant: NM_001008844.2(DSP):c.1778A>G (p.Asn593Ser)

ClinVar: 44867, https://www.ncbi.nlm.nih.gov/clinvar/variation/44867/

gnomAD: 0.0005695, https://gnomad.broadinstitute.org/variant/6-7571692-A-G

Case#: Case III-2, female, 74, early adulthood onset

DiseaseAssertion: Congenital Fiber Type Disproportion

FamilyInfo: Family A, late-onset weakness in her deceased mother (II-5) and maternal aunt (II-4), and lifelong weakness in her older sister (III-3)

CasePresentingHPOs: lower limb muscle weakness, gait disturbance, hearing loss, psoriasiform dermatitis, osteoarthritis, glaucoma, hypertension, muscle dystrophy, left ventricular diastolic dysfunction, hyperlordosis, genu recurvatum, proximal lower limb amyotrophy, foot dorsiflexor weakness, hip flexor weakness (HP:0007340, HP:0001288, HP:0000365, HP:0003765, HP:0002758, HP:0000501, HP:0000822, HP:0003560, HP:0025168, HP:0003307, HP:0002816, HP:0008956, HP:0009027, HP:0012515)

CaseHPOFreeText: Pes cavus and hammertor deformities, bilataeral steppage in gait,

CaseNotHPOs: N/A

CaseNotHPOFreeText: myotatic reflexes normal, ECG normal, normal NCS, no fibrillation potentials, sharp waves, or myotonic discharges

CasePreviousTesting: Analysis was negative for sequence variants affecting other congenital myopathy genes associated with CFTD pathology including ACTA1, RYR1, SEPN1, TPM2, and TPM3

CaseGenotypingMethod: neurological examination, serum creatine kinase (60 unit/L), nerve conduction studies, concentric needle electromyography (early recruitment of small polyphasic MUAP in diffuse pattern), electrocardiogram, echocardiogram, forced vital capacity (2.13% (76)), muscle biopsy, immunohistochemical analyses,

Variant: NM_000257.4(MYH7):c.484T>G (p.Tyr162Asp)

ClinVar: 525040 https://www.ncbi.nlm.nih.gov/clinvar/variation/525040/

CAID: N/A

gnomAD: absent

Case#: D26, female, 54 years

DiseaseAssertion: FDCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

ClinVar: 181267 https://www.ncbi.nlm.nih.gov/clinvar/variation/181267/

CAID: N/A

gnomAD: absent

Case: Case report, female, 41yo

CasePresentingHPOs: HP:0001270, HP:0002094, HP:0007340, HP:0010535, HP:0002540, HP:0003323, HP:0002015, HP:0100749, HP:0001662, HP:0005952 (motor delay, dyspnea, lower limb weakness, sleep apnea, inability to walk, progressive muscle weakness, dysphagia, chest pain, bradychardia, decreased pulmonary function)

HPOsFreeText: non-smoker, onset of neuromuscular disorders in early childhood, written language delay, difficulty completing exercise, dyspnea and lower limb weakness presenting during patient's first pregnancy (33yo), required mechanical ventilation machine, symptoms of skeletal muscle disorder began after delivery of first child, unable to get up without assistance, unable to climb stairs, required use of cane, walker, then eventually a wheelchair, episodes of paralysis in lower limbs, normal tone/bulk of arm muscles but bilateral weakness in shoulders and upper limbs (MRC scale of 3/5), intact fine finger movements, down-going toes, reduced perception of vibration in lower limbs, needle EMG showed tendency of myotonic potentials, muscle biopsy of left quadricep showed features of end-stage process consistent with chronic myopathy (Fig. 2A-D), forced vital capacity = 27%, forced expiratory volume per second = 29%

CaseNotHPOs: HP:0001513, HP:0040129 (obese, abnormal nerve conduction velocity)

NotHPOsFreeText: pronator drift, sensory deficit, ocular muscle involvement

FamilyInfo: mother died at 66yo due to heart attack associated with non-compaction cardiomyopathy, daughter (11yo) has signs of muscle disorders, congenital muscular torticollis, excessive growing pains, and underdeveloped muscles in half of body

CaseGenotypingMethod: WES, variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.1370T>G (p.Ile457Arg)

ClinVar: 560881, https://www.ncbi.nlm.nih.gov/clinvar/variation/560881/

gnomAD: absent

MultipleGeneVariants:

(1) SNCB Variant

Variant: NM_003085.5(SNCB):c.368C>A (p.Pro123His)

ClinVar: 7026, https://www.ncbi.nlm.nih.gov/clinvar/variation/7026/

gnomAD: 0.0001929, https://gnomad.broadinstitute.org/variant/5-176048219-G-T

(2) GDF6 Variant:

Variant: NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu)

ClinVar: 8371, https://www.ncbi.nlm.nih.gov/clinvar/variation/8371/

gnomAD: 0.001948, https://gnomad.broadinstitute.org/variant/8-97157413-G-T

Supplementary Data: S2 Table

Case 8: Spanish, 81yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.3056C>A (p.Thr1019Asn)

ClinVar: 195720, https://www.ncbi.nlm.nih.gov/clinvar/variation/195720/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23892799-G-T

CaseVII: Adolescent onset, 33 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002460, HP:0003394 (Proximal muscle weakness, Increased serum CK, Distal muscle weakness, Muscle cramps)

HPOsFreeText: GAA activity from dried blood spot: 0.20%, Forced Vital Capacity Seated: 5260 (112%), Plasma CK 2.5-5x Normal, Vacuoles in histology

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

Case6HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 1 pmol/punch/hr, GAA activity at 10% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

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

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

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

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

Variant2: NM_000152.4:c.2242dupG (p.Glu748Glyfs)

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

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

CaseAddInfo:

CaseOPOPD-53: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.23 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.1843G>A (p.Gly615Arg)

ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/

gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has the same genotype

CaseOPOPD-6: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.75 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

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

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

gnomAD: African 6.166e-5, Overall 1.602e-5 http://gnomad.broadinstitute.org/variant/17-78079570-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, 2 others have the same genotype

CaseOPOPD-44: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.51 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1222A>G (p.Met408Val)

ClinVar: 371235 https://www.ncbi.nlm.nih.gov/clinvar/variation/371235/

gnomAD: European (Non-Finnish) 1.790e-5, Overall 8.058e-6 http://gnomad.broadinstitute.org/variant/17-78082523-A-G

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 allele and One Pseudodeficency Mutation allele

CaseIP2-3: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.04 umol/hr/L, Serum CK at 809 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1082C>T (p.Pro361Leu)

ClinVar: 403712 https://www.ncbi.nlm.nih.gov/clinvar/variation/403712/

gnomAD: Latino 5.798e-5, Overall 1.203e-5 http://gnomad.broadinstitute.org/variant/17-78082294-C-T

Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

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

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant3: NM_000152.4:c.1726G>A (p.Gly576Ser)

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

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

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 2 and 3 are in trans

CaseOPOPD-39: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.56 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.841C>T (p.Arg281Trp)

ClinVar: 283894 https://www.ncbi.nlm.nih.gov/clinvar/variation/283894/

gnomAD: European (Non-Finnish) 4.051e-4, Overall 2.051e-4 http://gnomad.broadinstitute.org/variant/17-78081504-C-T

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

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

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

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPOPD-65: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.77 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.2185delC (p.Leu729Trpfs)

ClinVar: 370552 https://www.ncbi.nlm.nih.gov/clinvar/variation/370552/

gnomAD: Not in gnomAD

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has this genotype

Case#: Patient 17, female

CasePresentingHPOs: HP:0003236

CaseAddInfo: 38yo at onset, 39yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

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

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

VariantAllele2: NM_000152.4(GAA):c.2237G>A (p.Trp746Ter)

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

gnomAD: 8.301e-06, http://exac.broadinstitute.org/variant/17-78090814-G-A

Patient29: Female, 30 years onset

CasePresentingHPOs: HP:0001324, HP:0001288 (Muscle weakness, Gait disturbance)

HPOsFreeText: GAA activity 4% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient18: Female, 48 years report, 42 years onset

CasePresentingHPOs: N/A

HPOsFreeText: GAA activity 8.1% from leukocyte

CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient23: Male, 68 years report, 2.5 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 9.8% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0002240 (Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient4: Male, 5 years report, 1 year onset

CasePresentingHPOs: HP:0001640 (Cardiomegaly)

HPOsFreeText: GAA activity 3.5% from leukocyte

CaseNotHPOs: HP:0002098, HP:0001324, HP:0002240 (Respiratory distress, Muscle weakness, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: IOPD

Patient21: Male, 35 years report, 1y< years onset

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

CaseAddInfo: LOPD

Patient11: Male, 10 years report, 4 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 16.9% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient38: Male, 20 years report, 2 year onset

CasePresentingHPOs: HP:0001324, HP:0002098, HP:0002527 (Muscle weakness, Respiratory distress, Falls)

HPOsFreeText: GAA activity 2.7% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Case30: Female, 10 yr onset, 11 yr diagnosis, 16.4 yr report

CasePresentingHPOs: HP:0002650 (Scoliosis)

HPOsFreeText: Wheelchair used at 16 yr, Respiratory support used at 12 yr, FVC z-score sitting -8.07 (13% pred), 72% MRC Scale, 1560 CK U/l, 3.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts

Case15: Male, 8 yr onset, 4 yr diagnosis, 15.8 yr report

HPOsFreeText: FVC z-score sitting -2.65 (70% pred), FVC z-score supine -3.05 (65% pred), 93% MRC Scale, 1424 CK U/l, 7.8 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case12: Female, 5 yr onset, 7.8 yr diagnosis, 7.8 yr report

HPOsFreeText: FVC z-score sitting 0.62 (108% pred), FVC z-score supine 0.35 (104% pred), 100% MRC Scale, 1003 CK U/l, 11.6 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Patient10: Male, 45yo at diagnosis, 58yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:3200, enzyme (μmol/g/h) = 0.39 (3-20), mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: NIV not required

CaseAddInfo: 27yr disease duration, patient discontinued ERT, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Variant2: NM_000152.4(GAA):c.258dupC (p.Asn87Glnfs)

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

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

Patient20: Female, 46yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:12,800, enzyme (μmol/g/h) = 0.64 (3-20), NIV required before and after ERT

CaseNotHPOs:

NotHPOsFreeText: mobility aid not required

CaseAddInfo: 26yr disease progression, 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.2242dupG (p.Glu748Glyfs)

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

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78090813-T-TG

Patient19: Male, 54yo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:6400, enzyme (μmol/g/h) = 0.41 (3-20), NIV and mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 35yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Variant2: NM_000152.4(GAA):c.2242dupG (p.Glu748Glyfs)

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

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78090813-T-TG

Case13

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

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

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

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

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.1292_1295dupTGCA (p.Gln433Alafs*74)

ClinVar: 552165 https://www.ncbi.nlm.nih.gov/clinvar/variation/552165/

gnomAD: African 6.992e-5, Overall 4.293e-6 http://gnomad.broadinstitute.org/variant/17-78082592-C-CTGCA

CaseAddInfo: Infantile Onset Pompe Disease

Case92

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

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

Variant1: NM_000152.4:c.1143delC (p.Ala382Leufs*10)

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

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

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

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

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

CaseAddInfo: Adult Late Onset Pompe Disease, 1 other patient has the same genotype

Case71

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.2242dupG (p.Glu748Glyfs*48)

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

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

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

Case48

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

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

Variant: NM_000152.4:c.655G>A (p.Gly219Arg) (p.Glu176Argfs*45)

ClinVar: 189065 https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: African 4.024e-5, Overall 1.809e-5 http://gnomad.broadinstitute.org/variant/17-78079656-G-A

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

Case28

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.1099T>C (p.Trp367Arg)

ClinVar: 555820 https://www.ncbi.nlm.nih.gov/clinvar/variation/555820/

gnomAD: Not in gnomAD

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

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

gnomAD: East Asian 6.418e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78086424-C-T

CaseAddInfo: Infantile Onset Pompe Disease

Case17: Female, 49 years report

HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 314 meters, Forced Vital Capacity at 54%

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.1548G>A (p.Trp516Ter)

ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-G-A

CaseAddInfo: Late Onset Pompe Disease

Case26: Female, 65 years report

HPOsFreeText: 5 years of ERT completed, Forced Vital Capacity at 57%

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.1548G>A (p.Trp516Ter)

ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-G-A

CaseAddInfo: Late Onset Pompe Disease

Case27: Male, 71 years report

HPOsFreeText: 0.3 years of ERT completed, 6 Minute Walking Test at 348 meters, Forced Vital Capacity at 53%

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.2608C>T (p.Arg870Ter)

ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/

gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 http://gnomad.broadinstitute.org/variant/17-78092118-C-T

CaseAddInfo: Late Onset Pompe Disease

Case3: Female, Caucasian, United States, 8 days diagnosis, 2 weeks onset, 1.2 years report

CasePresentingHPOs: HP:0003236, HP:0002194, HP:0003749, HP:0003093, HP:0003273, HP:0003184, HP:0008796, HP:0006380, HP:0001435, HP:0003484, HP:0006589, HP:0003725, HP:0008981, HP:0001270, HP:0001290, HP:0002376 (Increased serum CK, Delayed gross motor development, Pelvic girdle muscle weakness, Limited hip extension, Hip flexion contractures, Decreased hip abduction, Externally rotated hips, Knee flexion contracture, Abnormality of the shoulder girdle musculature, Upper limb muscle weakness, Flaring of lower rib cage, Firm muscles, Calf muscle hypertrophy, Motor delay, Generalized hypotonia, Developmental regression)

HPOsFreeText: Had hyperCKemia since the second week of life (605 IU/L, day 8 of life; 513 IU/L, age 3 months), At 5 months she was unable to hold head up to 90 degrees in prone, unable to sit with slight support but unable to prop-sit, and unable to bear weight on hands in prone with AIMS score at the 10th percentile, PT evaluation at age 6 months revealed progression of delay in gross motor milestones, with AIMS score at the 3rd percentile, Unable to sit upright or unsupported and unable to push up on arms in prone, scored only 20% on Dimension B (Sitting) of the GMFM, Imbalanced weakness was evident in trunk and pelvic musculature with predominant active use of, and positioning in, hip flexion/abduction/external rotation in supine, prone and sitting, decreased use of hip extensors and abdominals, and limitation in the use of abdominal obliques for active trunk rotation, Adduction, Tightness in hip flexors, IT bands, and plantar flexors present, Weakness in abdominals, and in hip extension, ankle dorsiflexion, and ankle eversion persisted at 16 months after walking began, ALT 198 U/L (Normal 5–40 U/L), AST 139 U/L (Normal 15–41 U/L), ALP 248 U/L (Normal 24–170 U/L), Urinary Glc4 7.3 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

Patient6: 7yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA = 20 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 3mo at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Variant2: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

CasePD/VOUS-4: 2 weeks diagnosis

HPOsFreeText: GAA activity 5.3 (nmol · h−1 · mg−1), Mean percentage of normal 7.5%

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.664G>A (p.Val222Met)

ClinVar: 290223 https://www.ncbi.nlm.nih.gov/clinvar/variation/290223/

gnomAD: South Asian 5.393e-3, Overall 6.931e-4 http://gnomad.broadinstitute.org/variant/17-78079665-G-A

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

CasePD/VOUS-1: 3 weeks diagnosis

HPOsFreeText: GAA activity 3.6 (nmol · h−1 · mg−1), Mean percentage of normal 5.0%

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.664G>A (p.Val222Met)

ClinVar: 290223 https://www.ncbi.nlm.nih.gov/clinvar/variation/290223/

gnomAD: South Asian 5.393e-3, Overall 6.931e-4 http://gnomad.broadinstitute.org/variant/17-78079665-G-A

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

Case6: Male, 36 years onset, 45 years diagnosis, 68 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficiency)

HPOsFreeText: Lost ambulation at 54 years, Started invasive ventilation at 52 years, Started ERT given every other week at a dose of 20 mg/kg at 63 years for 56 months, Peak Anti-rhGAA antibodies at 1:51,200, FVC at 0.7/18 (L / % expected), MIP at 9 (cm H2O), MEP at 13 (cm H2O), Time off ventilation stayed constant at 240 min, Total Motor Function Measure from 49 to 35, 6MWT from 50 to 10 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

Case8: Female, 36 years onset, 43 years diagnosis, 60 years report, France

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

HPOsFreeText: Lost ambulation at 51 years, Started invasive ventilation at 53 years, Started ERT given every other week at a dose of 20 mg/kg at 55 years for 63 months, Peak Anti-rhGAA antibodies at 1:12,800, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 45 to 40, 6MWT stayed constant at 0 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

Case#: 2/b, age 11, age 5 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 2, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 105.01 NaG/AaGIA, 90.98% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

ClinVar: 932904

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

ClinVar: 279811

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 6/b, age 40, age 36 (report)

DiseaseAssertion: gray zone (Pompe Disease)

FamilyInfo: Family 6, no further information

CasePresenting HPOs: HP:0001288 (Impaired gait)

CaseHPOFreeText: Progressive worsening muscle weakness, vacuolar myopathy biopsy PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, the results of (NaG/AaGIA > 40 and %INH < 87) or (NaG/AaGIA < 40 and %INH > 87) are considered to be within a gray zone.

Variants:

Variant 1: NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

ClinVar: 550327

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

ClinVar: 4027

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 5/a, age 6, age 1 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 5, no further information

CasePresenting HPOs: HP:0001290, HP:0001639 (hypotonia, hypertrophic cardiomyopathy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 94.50 NaG/AaGIA, 94.31% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.1832G>A (p.Gly611Asp)

ClinVar: 371226

Variant 2:NM_000152.5(GAA):c.1832G>A (p.Gly611Asp)

ClinVar: 371226

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Patient8: Male, 1mo at diagnosis, 4mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, poor response to ERT, Pompe muscle pathology score = 3.5, Glycogen = 28.4 Vv(PAS + /mf)%, larger empty vacuoles = 46.8 Vv (LEV/mf)%, Autophagic vacuoles = 0,2 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

Patient4: Male, 2mo at diagnosis, 2.5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, poor response to ERT, Pompe muscle pathology score = 4.1, Glycogen = 40.3 Vv(PAS + /mf)%, larger empty vacuoles = 52.2 Vv (LEV/mf)%, Autophagic vacuoles = 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2213G>A (p.Trp738Ter)

ClinVar: 370222, https://www.ncbi.nlm.nih.gov/clinvar/variation/370222/

gnomAD: n/a

Variant2: NM_000152.4:c.delExon18

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

gnomAD: n/a

Patient11: male

CasePresentingHPOs: HP:0002546, HP:0001371

HPOsFreeText: CRIM positive, heart normalization, moderate periventricular white matter abnormalities (hypomyelination)

CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0000365

CaseAddInfo: variants in trans, symptom onset at birth, diagnosis at 12 days. Died at 78mo due to cardiorespiratory failure.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1942G>A (p.Gly648Ser)

ClinVar: 188902, https://www.ncbi.nlm.nih.gov/clinvar/variation/188902/

gnomAD: 0.0001018, http://exac.broadinstitute.org/variant/17-78086728-G-A

Variant2: NM_000152.4(GAA):c.2646+2T>A

ClinVar: 188924, https://www.ncbi.nlm.nih.gov/clinvar/variation/188924/

gnomAD: n/a

Patient26: Female

CasePresentingHPOs: HP:0004887, HP:0001270, HP:0001371

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, heart normalization

CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 3yo, diagnosis at 5yo, ERT at 8yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 0.000007972, http://gnomad.broadinstitute.org/variant/17-78082197-T-C

Patient14: male

CasePresentingHPOs: HP:0004887, HP:0040288, HP:0002546, HP:0000365

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:204.800, immunomodulation, infusion associated reaction, able to sit independently, partial heart normalization

CaseNotHPOs: HP:0001371

CaseAddInfo: homozygous variants in trans. Symptom onset, diagnosis and ERT at 4yo.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

gnomAD: n/a