4 missense mutations
Case#: One patient from Norway
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.223G>C (p.A75T)
Variant1ClinVarID: 222993
Variant1CAID: CA356994
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3/f
Case#: Patient 3, female, 18.1 months (age at diagnosis), 31 months (age at HSCT), 7 MRI + neuropsychological observations over the course of 16 years.
DiseaseAssertion: MPS-1H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 43.5 nmol/h/mg (Normal values: 11-43 nmol/h/mg)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: Yes
Variant1: c.979G>C (p.A327P)
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.979G>C (p.A327P)
Variant2ClinVarID: 167190
Variant2CAID: CA234128
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
PKMPS1P10
Case#: PKMPS1P10, 4 years old (age at presentation), female, Pakastani
DiseaseAssertion: MPS-I
FamilyInfo: One of her elder siblings died due to MPS-I and her parents were cousins.
CasePresentingHPOs: Coarse facial features (HP:0000256)
CaseHPOFreeText: Poor growth potential, underweight, stunted and widening of the wrist
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.784delC (p.H262Tfs*55)
Variant1ClinVarID: 956890
Variant1CAID: CA2802083
Variant2: c.784delC (p.H262Tfs*55)
Variant2ClinVarID: 956890
Variant2CAID: CA2802083
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
PKMPS1P2a
Case#: PKMPS1P2a, 8 years old (age at presentation), female, Pakastani
DiseaseAssertion: MPS-IH
FamilyInfo: Proband has an affected younger brother (PKMPS1P2b)
CasePresentingHPOs: On and off snoring, nasal congestion, failure to thrive, abdominal distension, recurrent respiratory infections, hepatomegaly (HP:0025267, HP:0001742, HP:0001508, HP:0003270, HP:0002788, HP:0002240)
CaseHPOFreeText: A liver span of 2 cm with firm consistency and a smooth surface. Smooth muscle infections.
CaseNotHPOs: Vomiting, headache (HP:0002013, HP:0002315)
CaseNotHPOFreeText: Fever, difficulty walking, normal facial features and normal eyes.
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.908T>C (p.L303P)
Variant1ClinVarID: N/A
Variant1CAID: CA355962537
Variant2: c.908T>C (p.L303P)
Variant2ClinVarID: N/A
Variant2CAID: CA355962537
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
24
Case#: Patient 24, born in 2009 (paper published in 2017), 8 months (age at first treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Cataract, retinopathy (HP:0000518, HP:0000488)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 48.88 ng/mol (48.75 weight matched enzyme reference assay)
CaseUrineGAGs: 0.28 DS/CS
CaseERT: Yes
CaseBMT: Yes, MUD
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
7
Case#: Patient 7, born in 2005 (paper published in 2017), 16 months (age at first treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 62.57 ng/mol (34.3 weight matched enzyme reference assay)
CaseUrineGAGs: 0.59 DS/CS
CaseERT: No
CaseBMT: Yes, Cord
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.386-2A>G
Variant2ClinVarID: 222994
Variant2CAID: CA356991
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
2
Case#: Patient 2, born in 2000 (paper published in 2017), 18 months (age at first treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 28 ng/mol (38 weight matched enzyme reference assay)
CaseUrineGAGs: 0.36 DS/CS
CaseERT: No
CaseBMT: Yes, MUD
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.979G>C (p.A327P)
Variant2ClinVarID: 167190
Variant2CAID: CA234128
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 6, 5 years old, Iranian
DiseaseAssertion: MPSI-H (Severe)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.05 µmol/g.h (Normal ranges: 10-50 µmol/g.h)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.590-17_607del (GFLNYY197-202)
Variant1ClinVarID: N/A
Variant1CAID: CA2586973524
Variant2: c.590-17_607del (GFLNYY197-202)
Variant2ClinVarID: N/A
Variant2CAID: CA2586973524
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
370.629 (7.5)13.9DS 3.4heterozygous PD: c.235G>A; p.A79TNormal examinationHS 2.7heterozygous PD: c.246C>G; p.H82Q
Case#:Patient Sample unique ID 37, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.629 (13.9) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 13.9 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 3.4 g/mol creatinine and HS 2.7 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:homozygous PD: c.235G>A; p.A79T (Normal examination)
Variant1ClinVarID:41682
Variant1CAID: CA000358
Variant2:heterozygous PD: c.246C>G; p.H82Q
Variant2ClinVarID:92637
Variant2CAID:CA220506
AdditionalVariants: None
ParentalGenotype:None provided
PreviouslyPublished:N/A
670.454 (5.9)8.8DS 4.2homozygous PD: c.235G>A; p.A79TNormal examinationHS 4.7homozygous PD: c.296C>T; p.T99I
Case#:Patient Sample unique ID 67, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.454 (5.9) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 8.8 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 4.2 g/mol creatinine and HS 4.7 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:homozygous PD: c.235G>A; p.A79T (Normal examination)
Variant1ClinVarID:41682
Variant1CAID: CA000358
Variant2: homozygous PD: c.296C>T; p.T99I
Variant2ClinVarID:53610
Variant2CAID:CA326991
AdditionalVariants:None
ParentalGenotype:None provided
PreviouslyPublished:N/A
Hurler disease
Case#: Patient 27, 4 months old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, dysostosis multiplex (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0000943)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 3.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1249_1275del (p.Thr417_His425del)
Variant1ClinVarID: 556156
Variant1CAID: CA658823291
Variant2: c.1249_1275del (p.Thr417_His425del)
Variant2ClinVarID: 556156
Variant2CAID: CA658823291
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 42, 1 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0002828, HP:0007957, HP:0000943)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 3.1% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1855C>T (p.Arg619Ter)
Variant1ClinVarID: 280976
Variant1CAID: CA2802455
Variant2: c.1855C>T (p.Arg619Ter)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 37, 1 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0002828, HP:0007957, HP:0000943)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 4.8% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1373T>C (p.Leu458Pro)
Variant1ClinVarID: N/A
Variant1CAID: CA355964255
Variant2: c.1373T>C (p.Leu458Pro)
Variant2ClinVarID: N/A
Variant2CAID: CA355964255
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 28, 8 months old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, dysostosis multiplex (HP:0000280, HP:0001433, HP:0007957, HP:0000943)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1273delC (p.His425Thrfs*15)
Variant1ClinVarID: 3391381
Variant1CAID: CA2586965976
Variant2: c.1273delC (p.His425Thrfs*15)
Variant2ClinVarID: 556156
Variant2CAID: CA2586965976
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 50, 2 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, hernia (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.238G>T (p.Val80Phe)
Variant1ClinVarID: N/A
Variant1CAID: CA355946451
Variant2: c.784delC (p.His262Thrfs*55)
Variant2ClinVarID: 956890
Variant2CAID: CA2802083
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 10, 1 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: Sibling of patient 11
CasePresentingHPOs: Coarse facial features, recurrent infections, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0002719, HP:0000943, HP:0001249, HP:0100790)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.531C>G (p.Phe177Leu)
Variant1ClinVarID: 2432729
Variant1CAID: CA2801983
Variant2: c.531C>G (p.Phe177Leu)
Variant2ClinVarID: 2432729
Variant2CAID: CA2801983
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 30, 8 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1373T>C (p.Leu458Pro)
Variant1ClinVarID: N/A
Variant1CAID: CA355964255
Variant2: c.1373T>C (p.Leu458Pro)
Variant2ClinVarID: N/A
Variant2CAID: CA355964255
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 51, 2 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, dysostosis multiplex (HP:0000280, HP:0001433, HP:0002828, HP:0000943)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.265G>C in the article - incorrect variant but unknown what the correct nomenclature is. Could be c.265C>G (p.Arg89Gly) or c.266G>C (p.Arg89Pro)
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.779C>T (p.Ser260Phe)
Variant2ClinVarID: 3895951
Variant2CAID: CA355962251
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
one girl
Case#: Patient 2, female, 18 months (age at diagnosis), 22 months (age at HSCT), weight of 12.1 kg (at HSCT), 5 years (age at report). Neurological development is not impaired.
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, kyphosis, abdominal distension, mild mitral regurgitation (HP:0000256, HP:0002808, HP:0003270, HP:0001653)
CaseHPOFreeText: Chronic hydrocephalus-VP-shunt
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Activity of alpha-L-iduronidase in leukocytes was normal from 5 months after cessation of ERT.
CaseUrineGAGs: Patient had normal excretion of total urine GAGs - but a small fraction of dermatansulfate remained detectable upon electrophoresis of total urinary GAGs.
CaseERT: Yes - 13 weeks of ERT before HSCT. Continued until day 50 of HSCT.
CaseBMT: Yes - interval diagnosis for HSCT (15 weeks). The donor was female and unrelated.
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1631_1640del
Variant2ClinVarID: N/A
Variant2CAID: CA1433071867
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler
Case#: 0.2% residual activity at 37 °C
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.5 ± 0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.979G>A (p.A327P)
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.979G>A (p.A327P)
ClinVarID: 167190
Variant2CAID: CA234128
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler
Case#: <0.1% residual activity at 37 °C
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: <0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.134del12 on paper but nomenclature is c.46_57del (p.Ser16_Ala19del)
Variant1ClinVarID: 92643
Variant1CAID: CA220509
Variant2: c.134del12 on paper but nomenclature is c.46_57del (p.Ser16_Ala19del)
ClinVarID: 92643
Variant2CAID: CA220509
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Bone Remodeling in an Mps-1h Girl after Hematopoietic Stem Cell Transplantation along with Enzymatic Replacement Therapy
PMID: 35619307
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
2-year-old male MPS1-H child
Case#: Male, 2-year old
DiseaseAssertion: MPS1-H
FamilyInfo: Not provided
CasePresentingHPOs: Not provided
CaseHPOFreeText: NA
CaseNotHPOs: Not provided
CaseNotHPOFreeText: NA
CaseEnzymeAssay: MPS1-H fibroblasts exhibited no activity of IDUAα (0.01 ± 0.02 nmol/mg/min); iPSC clones were devoid of IDUAα activity
CaseUrineGAGs: Not provided
CaseERT: Don't know
CaseBMT: Don't know
Variant1: NM_000203.5(IDUA):c.1073_1093del (p.His358_Thr364del)
Variant1ClinVarID:557260
Variant1CAID:
Variant2: NM_000203.4(IDUA):c.1205 G>A (p.Trp402Ter)
Variant2ClinVarID:11908
Variant2CAID:
ParentalGenotype: Not provided
PreviouslyPublished: Authors reference [30]: PMID: 31678774 DOI: 10.1016/j.scr.2019.101604
474-2a>g
Case#: Family 13, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.386-2A>G; c.474-2A>G in the paper
Variant1ClinVarID: 222994
Variant1CAID: CA356991
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
628del5
Case#: Family 9, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.540_544del (p.W180X); c.628del5 in the paper
Variant2ClinVarID: 3775043
Variant2CAID: CA2573332240
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
5 nonsense mutations
This paper was listed on the ClinVar entry for this variant; however it was only included to show that loss-of-function variants in IDUA are known to be pathogenic
5 Hurler/Scheie
Case#: Family 21, Pakistan
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1469T>C (p.L490P)
Variant2ClinVarID: 11919
Variant2CAID: CA220503
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
9
Case#: Infant #9, female.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.46 IDUA enzyme activity (Ref. 5.9–27.8 μmol/g protein/h)
CaseUrineGAGs: DMB/Cre. Ratio - 33.61, DS - 5.91, HS - 9.38, KS - 0.28 GAG quantifications (DMB/Cre ratio) and the normal reference values based on the age groups: <6 mos: <70.68 mg /mmol cre.; 6 mos–2 yrs: <46.80 mg /mmol cre.; 2–17 yrs: <20.98 mg /mmol cre.; and >18 yrs: <12.62 mg /mmol cre. Quantitative analyses of GAG-derived disaccharides (DS, S, or KS) by tandem mass spectrometry assay. The normal cut-off values: DS < 0.80 μg/mL; HS < 0.78 μg/mL; and KS < 7.90 μg/mL.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.300-3C>G
Variant1ClinVarID: 551563
Variant1CAID: CA549265042
Variant2: c.1874A>C (p.Y625S)
Variant2ClinVarID: 2910181
Variant2CAID: CA355965961
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
7
Case#: Infant #7, female.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 21.60 IDUA enzyme activity (Ref. 5.9–27.8 μmol/g protein/h)
CaseUrineGAGs: DMB/Cre. Ratio - 26.82, DS - 0.20, HS - 0.01, KS - 6.49 GAG quantifications (DMB/Cre ratio) and the normal reference values based on the age groups: <6 mos: <70.68 mg /mmol cre.; 6 mos–2 yrs: <46.80 mg /mmol cre.; 2–17 yrs: <20.98 mg /mmol cre.; and >18 yrs: <12.62 mg /mmol cre. Quantitative analyses of GAG-derived disaccharides (DS, S, or KS) by tandem mass spectrometry assay. The normal cut-off values: DS < 0.80 μg/mL; HS < 0.78 μg/mL; and KS < 7.90 μg/mL.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.76G>A (p.A26T)
Variant1ClinVarID: 712785
Variant1CAID: CA280110
Variant2: c.911delT (p.V304Gfs*13)
Variant2ClinVarID: 1184991
Variant2CAID: CA2573052265
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Identification and characterization of -3c–g acceptor splice site mutation in human α- l-iduronidase associated with mucopolysaccharidosis type IH/S
PMID: 10735634
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
The impact of laronidase treatment inotolaryngological manifestations of patientswith mucopolysaccharidosis
PMID: 26750310 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive
20026495
Case#: Patient F (female), diagnosed at 4 years and 6 months on the basis of clinical findings, an elevated urinary glycosaminoglycan level, and low α-l-iduronidase activity in leukocytes. Patient F was 104.0 cm tall (75th percentile).
DiseaseAssertion: MPS1-H/S
FamilyInfo: The patient is an older sibling who was diagnosed with the disease and has an affected younger brother.
CasePresentingHPOs: Coarse facial features, joint stiffness, thick skin, corneal clouding, hepatosplenomegaly, dysostosis multiplex (HP:0000280, HP:0001387, HP:0001072, HP:0007957, HP:0001433, HP:0000943)
CaseHPOFreeText: Moderate mitral insufficiency with thickened valve leaflets and anterior edge prolapse; mild left atrium thickening and increased pulmonary pressure were also present. Radiographic skeletal examination showed several signs of hip hypoplasia, ovoid shape of lumbar vertebral bodies, V-shaped distal ulnar and radial extremities, and short and broad metacarpal bones. Although she had normal intelligence, she developed obstructive hydrocephalus, which required shunting at 7 months of age.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Low α-l-iduronidase activity in leukocytes
CaseUrineGAGs: Elevated urinary glycosaminoglycan levels
CaseERT: Yes - Patient F started laronidase at 5 years of age, also at the standard dose. After 5 years of therapy, she was 138.0 cm tall (90th percentile), her liver and spleen volume had normalized, her skin had become less thickened, and her shoulder flexion and extension were moderately improved. Her dysostosis multiplex, cardiac function, and corneal clouding (visual acuity: 10/10) had stabilized but were not improved.
CaseBMT: N/A
Variant1: c.12205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1603C>T (p.L535F)
Variant2ClinVarID: 638076
Variant2CAID: CA355965038
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
27/F
Case#: Patient 27, female, Han origin, 9 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/S
CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Macrocephaly, Hernia (HP:0001263, HP:0000256, HP:0100790)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 3.4 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.98A>C (p.H33P)
Variant1ClinVarID: N/A
Variant1CAID: CA355945475
Variant2: c.1402+2T>G
Variant2ClinVarID: 553131
Variant2CAID: CA355964392
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
21/F
Case#: Patient 21, female, Han origin, 10 years old (age at diagnosis)
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula (HP:0001263, HP:0000256, HP:0011369)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 0.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1898C>T (p.S633L)
Variant1ClinVarID: 556406
Variant1CAID: CA355966010
Variant2: c.536C>G (p.T179R)
Variant2ClinVarID: 556358
Variant2CAID: CA355961718
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
36/F
Case#: Patient 36, female, Han origin, 5 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0000256, HP:0001387, HP:0001433, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Mongolian macula, Hernia, (HP:0001263, HP:0011369, HP:0100790)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.159C>A (p.C53X)
Variant1ClinVarID: 1458768
Variant1CAID: N/A
Variant2: c.1037T>G (p.L346R)
Variant2ClinVarID: 11927
Variant2CAID: CA256128
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
43/M
Case#: Patient 43, male, Han origin, 5 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Macrocephaly (HP:0001263, HP:0000256)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.300-3C>G
Variant1ClinVarID: 551563
Variant1CAID: CA549265042
Variant2: c.530dupT (p.Glu178ArgfsTer5) (Paper refers to the variant as c.531dupT, there is a typo in the article where all duplication variants are one base pair off)
Variant2ClinVarID: N/A
Variant2CAID: CA2586973520
AdditionalVariants: c.1037T>G (p.L346R)
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
2
Case#: Patient No. 2 (Table 1), Arabic Druze ethnic group, male, 1.15 years old (age at time of gene therapy), 100 IQ score, 2.40 years since gene therapy, 2 years since latest visit
DiseaseAssertion: MPS-IH
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: Yes
Variant1: c.192C>A (p.Y64X)
Variant1ClinVarID: 11914
Variant1CAID: CA256113
Variant2: c.192C>A (p.Y64X)
Variant2ClinVarID: 11914
Variant2CAID: CA256113
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
7
Case#: Patient No. 7 (Table 1), Black race, male, 1.71 years (age at time of gene therapy), 80 IQ score, 1.73 years since gene therapy (1.5 years since latest visit)
DiseaseAssertion: MPS-IH
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: Yes
Variant1: c.923_926delTGCC (p.L308HfsX8)
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.923_926delTGCC (p.L308HfsX8)
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome
PMID: 34788506
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
distinct mutant IDUA alleles
Case#: Patient 32, Italy
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1225G>A (p.G265R)
Variant2ClinVarID: 1084956
Variant2CAID: CA91169920
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
missense mutations
Case#: Patient 82, Turkey
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1469T>C (p.L490P)
Variant2ClinVarID: 11919
Variant2CAID: CA220503
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
missense mutations
Case#: Patient 10, Italy
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1603C>T (p.L535F)
Variant2ClinVarID: 638076
Variant2CAID: CA355865038
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
missense mutations
Case#: Patient 65, Spain
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.979G>C (p.A327P)
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.1154C>G (p.P385R)
Variant2ClinVarID: 556024
Variant2CAID: CA355963438
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Patient of family E
Case#: Family E proband, female, 18 months old (age of diagnosis), 11 years old (age of death), Tunisia.
DiseaseAssertion: MPS1-H
FamilyInfo: No affected family members (See Fig. 1), parents were 1st degree relatives (See Table 1). The family benefited from a prenatal diagnosis showing a normal enzymatic activity (3.5 nmol/h/mg) (usual values: 1-5).
CasePresentingHPOs: HP:0001999, HP:0030799, HP:0002652, HP:0000687, HP:0030812, HP:0012471, HP:0000574, HP:0001537, HP:0001653, HP:0002673, HP:0001433, HP:0001640, HP:0004322 (Abnormal facial shape, scaphocephaly, skeletal dysplasia, widely spaced teeth, enlarged tonsils, thick lips, bushy eyebrows, umbilical hernia, mitral valve regurgitation, coax valga, hepatosplenomegaly, cardiomegaly, short stature
CaseHPOFreeText: Compression of the medulla
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity (0.5 nmol/h/mg) (usual values: 1-5 nmol/h/mg).
CaseUrineGAGs: glycosaminoglycans (125 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.530T>C (p.F177S)
Variant1ClinVarID: N/A
Variant1CAID: CA355961706
Variant2: c.530T>C (p.F177S)
Variant2ClinVarID: N/A
Variant2CAID: CA355961706
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: D349N
Variant1ClinVarID: 92623
Variant1CAID: CA220497
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Insights into Mucopolysaccharidosis I from the structure and action of α-L-Iduronidase
PMID: 24036510
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Why Insufficient: Variants are not linked to probands. This paper is assessing IDUA mutations on the structure of alpha-L-iduronidase. Therefore they are pulling common IDUA variants and using them to assess structure, rather than investigating how a variant has impacted a proband.
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: H82Q
Variant1ClinVarID:
Variant1CAID: CA355946477
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: M133I
Variant1ClinVarID:
Variant1CAID: CA91166179
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Abnormal
Case#: No additional case information provided.
DiseaseAssertion: Not specified
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Abnormal
CaseUrineGAGs: Normal
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1225G>A (p.G409R)
Variant1ClinVarID: 1084956
Variant1CAID: CA91169920
Variant2: c.1757C>T (p.S386F)
Variant2ClinVarID: 571910
Variant2CAID: CA2802396
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Abnormal
Case#: No additional case information provided.
DiseaseAssertion: Not specified
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Abnormal
CaseUrineGAGs: Normal
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1148G>A (p.R383H)
Variant1ClinVarID: 558189
Variant1CAID: CA2802205
Variant2: c.112C>A (p.R89S)
Variant2ClinVarID: 2432781
Variant2CAID: CA355945526
AdditionalVariants: c.250G>A (p.G48S), ClinVarID:726495, CAID:CA2801152
ParentalGenotype: N/A
PreviouslyPublished N/A
Abnormal
Case#: No additional case information provided
DiseaseAssertion: MPSI-H/S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Abnormal
CaseUrineGAGs: Normal
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11909
Variant1CAID: CA220498
Variant2: c.1577T>C (p.L526P)
Variant2ClinVarID: 567566
Variant2CAID: CA2802300
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient #3 (see Table 2), male, 15 months old (age at diagnosis), 5 years old (age at report).
DiseaseAssertion: MPS-I
FamilyInfo: Born to a consanguineous family
CasePresentingHPOs: Macrocephaly, corneal clouding, hearing loss (HP:0000256, HP:0007957, HP:0000365)
CaseHPOFreeText: Normal intelligence
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: α-L-iduronidase 15.6 pmol/spot. The activity of this enzyme is below its reference (200–2600 pmol/spot).
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1A>C (p.M1L)
Variant1ClinVarID: 550458
Variant1CAID: CA355945204
Variant2: c.469T>C (p.S157P)
Variant2ClinVarID: N/A
Variant2CAID: CA355961573
AdditionalVariants: N/A
ParentalGenotype: Variant c.1A>C was paternally inherited and variant c.469T>C was maternally inherited.
PreviouslyPublished N/A
genotypes of MPS I patients from 35 published studies papers
This is a review article that focuses on the prevalence of IDUA variants. The IDUA variants are not linked to specific patients or patient descriptions.
c.1728-1G > C
1 individual was reported to have this variant from the cohort UK cohort of 145 people.
Genotype: NM_000203.3 c.1205G>A p.(Trp402Ter) c.1728-1G>C
HPOFreeText: Phenotype: Sev: 1 (H) "classification of a “severe” phenotype was based on the presence of one or more of the following: presentation with clinical features of MPS I and diagnosis before 12 months of age; significant developmental delay in a child with clinical features of MPS I under 30 months of age; sibling of a child with MPS I also classified as “severe phenotype.”"
GenotypingMethod: bidirectional Sanger sequencing of the IDUA gene. IDUA exons and adjacent intron regions were amplified by PCR reactions and then sequenced
106
Case#: Pt 106 , Age 24 years, Female, DiseaseAssertion: MPS1 Scheie syndrome. FamilyInfo: NA CasePresentingHPOs: NA CaseHPOFreeText: NA CaseNotHPOs: NA CaseNotHPOFreeText: NA
CaseEnzymeAssay: Low leukocyte IDUA enzyme activity CaseUrineGAGs: NA CaseERT: No CaseBMT: No Variant1: p.R383H Variant1ClinVarID: 558189 Variant1CAID: Variant2:p.W402X Variant2ClinVarID: 11908 Variant2CAID: CA220498 AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA
207
Case#: 207 5.9 yrs male, age at initial diagnosis 2.6 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 3 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months
CaseBMT: No PreviouslyPublished Don't know Variant1:p.Q70X Variant1ClinVarID: 11909 Variant1CAID: CA204563 Variant2:p.W402X Variant2ClinVarID: 11908 Variant2CAID: CA220498
Pt2
Case#: Pt2, Male, 15 months (diagnosis), 15 months (onset)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: N/A Pedigree (Figure 4Pt2)
CasePresentingHPOs: HP:0000280, HP:0000365, HP:0001654, HP:0100814, (Coarse face, Hearing Loss, Valvular heart disease, Dermal melanocytosis)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0007957, HP:0001387, HP:0001433, (Cornea clouding, Joint stiffness, Hepatosplenomegaly)
CaseNotHPOFreeText: Long bone deformation, Spinal deformation, Inguinal or Umbilical hernia
CaseEnzymeAssay: α-L-iduronidase 0.06 (dried blood spots, normal >1.32 µM/h)
CaseUrineGAGs: Urine heparan sulfate 55.44 (mg/mmol creatinine) {0.65-3.51}
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Not Provided.
Variant1: c.1190-10C>A
Variant1ClinVarID: 950888
Variant1CAID: CA1139658405
Variant2: c.1190-10C>A
Variant2ClinVarID: 950888
Variant2CAID: CA1139658405
AdditionalVariants: N/A
ParentalGenotype: Both parents are homozygous for not having the c.1190-10C>A variant (figure 4 Pt 2)
PreviouslyPublished: N/A
Pt1
Case#: Pt1, Male, 20 months (diagnosis), 20 months (onset)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: N/A Pedigree (Figure 4Pt1)
CasePresentingHPOs: HP:0000280, HP:0007957, HP:0001654, HP:0100814, (Coarse face, Cornea clouding, Valvular heart disease, Dermal melanocytosis)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0001387, HP:0000365, HP:0001433, (Joint stiffness, Hearing loss, Hepatosplenomegaly)
CaseNotHPOFreeText: Long bone deformation, Spinal deformation, Inguinal or umbilical hernia
CaseEnzymeAssay: α-L-iduronidase 0.17 (dried blood spots, normal >1.32 µM/h)
CaseUrineGAGs: Urine heparan sulfate 8.26 (mg/mmol creatinine) {<0.67}
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Not Provided.
Variant1: c.1190-10C>A
Variant1ClinVarID: 950888
Variant1CAID: CA1139658405
Variant2: c.1190-10C>A
Variant2ClinVarID: 950888
Variant2CAID: CA1139658405
AdditionalVariants: N/A
ParentalGenotype: Both parents are homozygous for not having the c.1190-10C>A variant (figure 4 Pt 1)
PreviouslyPublished: N/A
Patient 1
Case#: Patient 1, male, 1 year old (age at diagnosis), 2 years old (age when deceased - due to a severe respiratory infection)
DiseaseAssertion: MPS I-H
FamilyInfo: Parents had a consanguineous marriage
CasePresentingHPOs: Coarse facial features, corneal clouding, hepatosplenomegaly, skeletal dysplasia, global developmental delay (HP:0000280, HP:0007957, HP:0001433, HP:0002652, HP:0001263)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.252insC (current nomenclature: c.252dup)
Variant1ClinVarID: N/A
Variant1CAID: CA3060586149
Variant2: c.252insC (current nomenclature: c.252dup)
Variant2ClinVarID: N/A
Variant2CAID: CA3060586149
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Lower Exposure to Busulfan Allows for StableEngraftment of Donor Hematopoietic Stem Cells inChildren with Mucopolysaccharidosis Type I: A CaseReport of Four Patients
PMID: 32781600 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive
10 MPS I patients
Case#: MPS 1 patient
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1858G>T (p.V620F)
Variant1ClinVarID: 1067173
Variant1CAID: CA355965934
Variant2: c.1858G>T (p.V620F)
Variant2ClinVarID: 1067173
Variant2CAID: CA355965934
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
10 MPS I patients
Case#: MPS 1 patient
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1650+5G>A
Variant2ClinVarID: 92634
Variant2CAID: CA220504
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
P2
Case#: P2, Female, 8.7 years (diagnosed), 10.7 (report), 21 kg (weight), 122 cm (height), Algerian
DiseaseAssertion: Scheie Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001999, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Facial Dysmorphic Features, Multiple Dysostosis, Hernia(Ombelical), Deafness(bilateral transmission), Corneal Opacity, Hydrocephalus)
CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency & Aortic Insufficiency)
CaseNotHPOs: HP:0001249, HP:0002240 (Mental Retardation, Joint Stiffness)
CaseNotHPOFreeText: HM/HSM
CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)
CaseUrineGAGs: GAG quantitation 47 (fold change to the reference range mean according to age)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Direct DNA Fragments Sequencing
Variant1: c.1598C>G (p.Pro533Arg)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.Pro533Arg)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Implementation of an Affordable Method for MPS Diagnosis from Urine Screening to Enzymatic Confirmation: Results of a Pilot Study in Morocco
PMID: 32162878
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Mutation analysis and clinical characterization of Iranian patients with mucopolysaccharidosis type I
PMID: 31386236
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
14
Case#: 14, Male, 0.7 years (diagnosed), 8.5 years (report), 9.5 kg (weight), 73 cm (height), Iranian
DiseaseAssertion: Hurler-Scheie Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001999, HP:0100790 (Facial Dysmorphic Features, Hernia)
CaseHPOFreeText: HM/HSM
CaseNotHPOs: HP:0001249, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 0.6 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 6.4 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.Y109H
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
9
Case#: 9, Female, 0.7 years (diagnosed), 1.2 years (report), 6.8 kg (weight), 69 cm (height), Iranian
DiseaseAssertion: Hurler-Scheie Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0100790 (Hernia)
CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea
CaseNotHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 0.97 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 7.21 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.Y109H
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Patient 2662, northern European origin, 11 years old (age of diagnosis), 22 years old (age at report), male, attended special schools until 15 years old, has not attained the ability to read and write, and has an increasingly poor memory.
DiseaseAssertion: MPS-1H/S, intermediate
FamilyInfo: Two affected younger sisters with MPS1 who presumably have the same R89Q/1060+2t-*-c genotype. he youngest sister died of bronchopneumonia at 22 mo of age. His second sister presented at 2 years and 6 mo of age with good general health, apart from upper respiratory tract infection, coarse facial features, enlarged liver and spleen, and limitation of elbow extension. This sister is now 20 years of age, has coarse facial features and joint limitations, is obese, and has a short stature. She is "bright" and able to live in her own flat with visiting help.
CasePresentingHPOs: Intellectual disability, memory impairment, limited motor development, severe joint contractures, short stature, obesity, macrocephaly, coarse facial features, hearing impairment, visual impairment (HP:0001249, HP:0002354, HP:0002194, HP:0002828, HP:0004322, HP:0001513, HP:0000256, HP:0000280, HP:0000365, HP:0000505)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Fibroblasts with two monoclonal antibodies detected 7%-10% of the normal levels of IDUA protein compared with only 1.5% of IDUA protein in a R89Q/W402X compound heterozygote
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.266G>A (p.R89Q)
Variant1ClinVarID: 11922
Variant1CAID: CA256124
Variant2: c.972+2T>C (1060+2T>C)
Variant2ClinVarID: N/A
Variant2CAID: CA355962890
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
9
Case#: Patient 9 (see Table 1), 5 years old - deceased (age at report), 1 year old (age at onset), female, height of 102 cm, weight of 18 kg, located at Mahdia: Touristic region.
DiseaseAssertion: MPS1 - severe
FamilyInfo: Parents were 1st cousins (see Table 2), aged 50 yrs (M) and 62 yrs (F).
CasePresentingHPOs: HP:0004322, HP:0010864, HP:0001537, HP:0000687, HP:0030812, HP:0001999, HP:0007957, HP:0000943 (Short stature, severe intellectual disability, umbilical hernia, widely spaced teeth, enlarged tonsils, facial dysmorphia, corneal clouding, dysostosis multiplex)
CaseHPOFreeText: Pigmented skin
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 0.020 μKat/kg
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1882C>T (p.R628X)
Variant1ClinVarID: 550421
Variant1CAID: CA2802462
Variant2: c.1882C>T (p.R628X)
Variant2ClinVarID: 550421
Variant2CAID: CA2802462
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4
Case#: Patient 4 (see Table 1), 9 years - deceased (age at report), 7 months (age at onset), male, height of 107 cm, weight of 19 kg, location at Gabes: Industrial region.
DiseaseAssertion: MPS1 - severe
FamilyInfo: One affected siblings (Patient 5), parents were 1st cousins (see Table 2) aged 55 yrs (M) and 65 yrs (F).
CasePresentingHPOs: HP:0004322, HP:0001999, HP:0000924, HP:0007957, HP:0001537, HP:0010864 (Short stature, abnormal facial shape, skeletal abnormality, corneal clouding, umbilical hernia, severe intellectual disability)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity: 0.018 μKat/kg
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
8-year-old girl
Case#: Female, 6 years old (age of onset), 8 years old (age at report). Developmentally normal at 6 years old but had a 1-year long history of painful and stiff joints. Her weight was in the 5th percentile, height in the 3rd percentile, and head circumference in the 10th percentile for her age group.
DiseaseAssertion: MPS1-S
FamilyInfo: The patient's parents are second cousins. She has two healthy brothers.
CasePresentingHPOs: Joint stiffness, recurrent otitis media, snoring, joint contractures, carpal tunnel syndrome (HP:0001387, HP:0000403, HP:0025267, HP:0100790, HP:0012185)
CaseHPOFreeText: Painful joints affecting the hands, wrists, knees, elbows, and shoulders. At 8 years old, she had second and third finger numbness. Flexion contractures in distal and proximal interphalangeal joints, wrists, and restricted joint mobility was observed. Echocardiogram showed thickening of the mitral and aortic valves, and brain magnetic resonance imaging demonstrated increased signal in the white matter surrounding dilated perivascular spaces.
CaseNotHPOs: Coarse facial features, cardiac murmurs, hernias (HP:0000256, HP:0030148, HP:0100790)
CaseNotHPOFreeText: Organomegaly
CaseEnzymeAssay: 1 nmol/h/mg (reference range, 14-41 nmol/h/mg)
CaseUrineGAGs: Excess heparan and dermatan sulfate
CaseERT: Enzyme replacement therapy was initiated. Improvements in hand mobility and joint size were noted, as well as less joint discomfort.
CaseBMT: N/A
Variant1: c.1039A>C (p.S347R)
Variant1ClinVarID: 1067172
Variant1CAID: CA355963126
Variant2: c.1039A>C (p.S347R)
Variant2ClinVarID: 1067172
Variant2CAID: CA355963126
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Two novel mutations causing mucopolysaccharidosis type I detected by single strand conformational analysis of the alpha-L-iduronidase gene
annotating here sice the article is only available as a PDF.
Case#: Clarke Patient 3
DiseaseAssertion: MPS I, severe
FamilyInfo: father and mother were het carriers
CasePresentingHPOs:
CaseHPOFreeText: severe clinical phenotype with presentation in the first year of life and currently at age two has received bone marrow transplantation
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: SSCP, restriction enzyme digestion
PreviouslyPublished: n/a
Variant: c.820G>T (p.Glu274Ter); Q70X phase confirmed
CAID: CA355962341
SupplementalData: n/a
Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree
PMID: 28649516
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome)
PMID: 21037085
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Hurler phenotype in a patient
Case#: 22-month-old Norwegian female patient
DiseaseAssertion: MPS-H
FamilyInfo: Mother and father received parental testing.
CasePresentingHPOs: Joint stiffness (HP:0001387)
CaseHPOFreeText: She had a tendency to fall without normal protective reactions. Typical facial appearance and other clinical findings were suggestive of MPS I Hurler, and this diagnosis was also supported by X-ray images which showed characteristic skeletal changes. Motor development appeared slightly delayed, while intellectual development was considered to be normal.
CaseNotHPOs: Corneal clouding (HP:0007957)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.006 μmol phenol/18 h/mg protein. Normal range of IDUA activity (n = 52, healthy volunteers): 0.143–0.351 μmol phenol/18 h/mg protein.
CaseUrineGAGs: Urinary GAG excretion - 101 mg GAG/mmol creatinine. The patient demonstrated increased excretion of GAGs, which were identified as HS and DS. Normal age adjusted range of urinary GAG excretion: 14–34 mg GAG/mmol creatinine.
CaseERT: The patient was initiated on enzyme replacement therapy (ERT) with weekly infusions of recombinant α-l-iduronidase 100 IE/kg
CaseBMT: The patient successfully received hematopoietic stem cell transplantation (HSCT) 4 months after ERT.
Variant1: c.1727+3G>C
Variant1ClinVarID: 4817926
Variant1CAID: CA91171181
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: Mother: c.208C>T (p.Q70X); 0.071 μmol phenol/18 h/mg protein (IDUA activity). Father: c.1727+3G>C; 0.079 μmol phenol/18 h/mg protein (IDUA activity).
PreviouslyPublished N/A
Successful pregnancy and breastfeeding in a woman with mucopolysaccharidosis type I while receiving laronidase enzyme replacement. therapy
PMID: 25864295
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
8
Case#: Patient 8, male
DiseaseAssertion: MPS I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Low IDUA enzyme activity 1.50 (Ref. 4.87 ~ 54.70 μmol/g protein/h)
CaseUrineGAGs: Negative GAG tests
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1081G>A (p.A361T)
Variant1ClinVarID: 92624
Variant1CAID: CA145865
Variant2: c.1395delC (p.G466Afs*?)
Variant2ClinVarID: 929236
Variant2CAID: CA549264595
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Epidemiology of Mucopolysaccharidoses Update
PMID: 33578874
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
15
Case#: Patient 15 (see Table 2), 38 weeks, 1 day (Gestational age)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Inguinal hernia (HP:0000023)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.23 nmol x mg-1 × hr-1
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.494-1G > A
Variant1ClinVarID: 557942
Variant1CAID: CA355961634
Variant2: c.494-1G > A
Variant2ClinVarID: 557942
Variant2CAID: CA355961634
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
26
Case#: Patient 26, male, 1 year (age at presentation).
DiseaseAssertion: MPS1-H
FamilyInfo: Consanguinity in the family not present for this patient.
CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, intellectual disabilities, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0010864, HP:0001744)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1855C>T (p.R619X)
Variant1ClinVarID: 280976
Variant1CAID: CA2802455
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
108 MOR.V. 0,01 DBS NM_000203.5:c.[208C>T];[1029C>A] Severe C
Case#: Patient 108, Central district of the Russian Federation
DiseaseAssertion: MPS1, Severe
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: IdA activity in DBS=0,01 DBS, severe phenotype, hyperexcretion of urine heparan and dermatan sulfate
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: Electrophoresis of urine GAGs and measurement of lysosomal enzyme activity in peripheral blood leukocytes or DBSs were performed for all patients with suspected MPS I
GenotypingMethod: The 14 exons and exon–intron boundaries of the IDUA gene were amplified from DNA samples. Sanger sequencing of each one of the 14 exons was performed. PCR products containing mutations were re-sequenced in both directions. The mutations were further confirmed where possible by restriction analysis (data not shown).
PreviouslyPublished:
Variant: NM_000203.5:c.[208C>T];[1029C>A]
ClinVar: 222997
CAID: CA356984
SupplementalData: n/a
Anthropometric data of 14 patients with mucopolysaccharidosis I: retrospective analysis and efficacy of recombinant human alpha-L-iduronidase (laronidase)
PMID: 19783188
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Agreement between the results of meta-analyses from case reports and from clinical studies regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I who initiated enzyme replacement therapy in adult age: An example of case reports meta-analyses as an useful tool for evidence-based medicine in rare diseases
Free, full-text NOT available. Full text was retrieved via a university account, and the free PubMed abstract was annotated.
This paper describes a meta-analysis of previously published data for 11 patients. PMID's for prior published reports:
25864295, 21482163, 22303797, 21167740, 19894140, 18792977, 18546328, 16601901
The above PMID's are all included in the IDUA Excel file.
Three cited manuscripts do not have a PMID and are not included in the IDUA Excel file. Links to these papers are provided below:
https://doi.org/10.1016/j.farma.2010.11.005 (in Spanish)
1
Case#: Patient 1 (see Table 2), female, 18.6 years old (age at report), 5.9 years (years of treatment), 6 surgeries.
DiseaseAssertion: MPS1-HS
FamilyInfo: N/A
CasePresentingHPOs: HP:0002176, HP:0002360 (Spinal cord compression, sleep abnormality)
CaseHPOFreeText: Psychiatric problems
CaseNotHPOs: HP:0000238 (Hydrocephalus)
CaseNotHPOFreeText: Shunt Placement
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.712T>A (p.L238Q) CDNA and protein change do not match. Known variant p.L238Q has a CDNA change of c.713T>A.
Variant1ClinVarID: 265418
Variant1CAID: CA2802065
Variant2: c.63delC (p.P22Rfs*86) Known HGVS nomenclature is c.65del as there is a run of 5 C's.
Variant2ClinVarID: 929238
Variant2CAID: CA437911597
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Mutational Analysis of the alpha-L-iduronidase gene in three Egyptian families: identification of three novel mutations and five novel polymorphisms
PMID: 19839758
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
older sibling
Case#: OS of sibship 7, female, 4.3 years old (age at diagnosis), 4.5 years old (age at ERT enrollment), 5.5 years (duration of ERT)
DiseaseAssertion: MPS1-HS
FamilyInfo: Affected YS (YS of sibship 7)
CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0001270 (Corneal opacity, dysostosis, joint contractures, cognitive impairment, motor impairment)
CaseHPOFreeText: Cardiac disease, somatic impairment
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes - After 5 years of ERT, cardiac symptoms stabilized, and musculoskeletal symptoms, motor development, and corneal clouding progressed.
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: (L564fsx) No CDNA change provided.
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
MPS IH patients
Case#: Patient 3
DiseaseAssertion: MPS1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1487C>G (p.P496R)
Variant2ClinVarID: 496861
Variant2CAID: CA2802275
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Molecular characterization of a large cohort of Mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis Study (IMPRESsion)
PMID: 35005816
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
High Precision Newborn Screening for Mucopolysaccharidosis Type I by Enzymatic Activity followed by Endogenous, Non-Reducing End Glycosaminoglycan Analysis
PMID: 39645522
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
The proband (III 4) was a 46-year-oldmiddle-aged man who was diagnosed with HCM at theage of 18
Case III-4: proband, Chinese, male, 46yo, diagnosed with HCM at 18yo
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0010872, HP:0011713 (exertional dyspnea, chest pain, ST segment depression, T wave inversion, left bundle branch block)
CaseHPOFreeText: electrocardiography showed abnormal Q wave, atrium expansion, ventricular septum thickness = 13mm, left ventricular posterior wall = 10mm, left ventricular end-diastolic diameter = 52mm, left ventricular ejection fraction = 55%, small amount of tricuspid regurgitation
FamilyInfo: study assessed 3 generations of this family (22 individuals), all participants were genotyped, 8 family members were carriers of variant (p.Asn391Thr) 6 of which were diagnosed with HCM, four individual in the family died (3 of which had been diagnosed with HCM)
CasePreviousTesting: Full testing of 7 sarcomere genes (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional gene testing (MYH6, TTN, TNNC1, PRKAG2, LAMP2, GLA, CSPR3, MYOZ2, JH2, ACTN2, CAV3, LDB3, VCL, PLN, MYPN, NEXN, CALR3, ANKRD1), electrocardiogram, echocardiogram
CaseGenotypingMethod: genomic DNA collected from peripheral venous blood leukocytes, high-throughput sequencing used to sequence 26 genes (exons and 5bps of upstream and downstream intron sequences), amplified via PCR
Variant: NM_000257.3:c.1172A>C
CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191
gnomAD: n/a
II-11 Male
Case III-11: Male, 32yo, Chinese, unknown age of diagnosis
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0005135 (abnormal T wave)
CaseHPOsFreeText: ventricular septum thickness = 16mm, posterior wall of left ventricle = 10mm
CaseNotHPOs: HP:0012250 (ST segment depression)
CaseNotHPOsFreeText: no clinical manifestation, abnormal Q wave
CasePreviousTesting: same as proband
CaseGenotypingMethod: same as proband
Variant: NM_000257.3:c.1172A>C
CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191
gnomAD: n/a
III-16 Male
Case III-16: Male, 17yo, Chinese, diagnosed at 16yo
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0002875, HP:0100749, HP:0100576, HP:0012250 (exertional dyspnea, chest pain, amaurosis fugax, ST segment depression)
CaseHPOFreeText: abnormal Q wave, interventricular septum = 21mm, posterior wall of left ventricle = 10mm, outflow obstruction
CaseNotHPOs: HP:0005135 (abnormal T wave)
CasePreviousTesting: same as proband
CaseGenotypingMethod: same as proband
Variant: NM_000257.3:c.1172A>C
CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191
gnomAD: n/a
proband
Case1:
DiseaseAssertion: Hypertrophic cardiomyopathy
CaseHPOFreeText: severe congestive heart failure
GenotypingMethod: bi-directional Sanger sequencing
Variant: NM_000257.4:c.2191C>T
ClinVar: 181176
CAID: CA011922
gnomAD: not found
CaseMYH7-8: Japan, Asian
CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo:
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.
Variant: NM_000257.3:c.1357C>T (p.Arg453Cys)
ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: Not in gnomAD
MYH7
Case120682: 62 year old Caucasian female
DiseaseAssertion: LVNC
FamilyInfo: family history was negative for cardiomyopathy or CHF, one daughter was noted to have a persistent high resting pulse
CasePresentingHPOs:
CaseHPOFreeText: first degree AV-block on ECG and prominent trabeculations at the left ventricular (LV) apex, mild aortic regurgitation
CaseNotHPOs:
CaseNotHPOFreeText:pulmonary hypertension
CasePreviousTesting: 41 cardiomyopathy-associated genes
GenotypingMethod: next generation sequencing and variant analysis, WES or WGS
Variant: NM_000257.4:c.732+1G>A
ClinVar: 14127
CAID: CA016715
gnomAD: 0.00005437 East Asian
Supplementary Material 4
Case M-18: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)
ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: n/a
Supplementary Material 4
Case M-2: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.611G>A (p.Arg204His)
ClinVar: 43095, https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/
gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23900998-C-T
Supplementary Material 4
Case M-8: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091, https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T
Supplementary Material 4
Case M-25: Japanese
DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)
CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)
CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing
Variant: NM_000257.3:c.2596T>C
CAID: CA389048059, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048059
gnomAD: n/a
Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice
PMID: 23896226
Gene: MYH7
HGNC: 7577
"Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C."
Supplementary Data: Table S3
Case 140:
DiseaseAssertion: left ventricular noncompaction
CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)
CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1
CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.
CaseGenotypingMethod: WES, variant enrichment analysis
Variant: NM_000257.3(MYH7):c.3286G>T (p.Asp1096Tyr)
ClinVar: 42953, https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/
gnomAD: 0.0001414, https://gnomad.broadinstitute.org/variant/14-23890217-C-A
MultipleGeneVariants:
(1) SDHA Variant:
Variant: NM_004168.3(SDHA):c.830C>T (p.Thr277Met)
ClinVar: 222817, https://www.ncbi.nlm.nih.gov/clinvar/variation/222817/
gnomAD: 0.00008359, https://gnomad.broadinstitute.org/variant/5-231050-C-T
(2) TTN Variant:
Variant: p.32991_32992del no ClinVar or CAID
Supplementary Data: Table S3
Case: 63
DiseaseAssertion: left ventricular noncompaction
CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)
CaseHPOFreeText: suspected LVNC, >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio < 2.3:1
CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.
CaseGenotypingMethod: WES, variant enrichment analysis
Variant: NM_000257.3(MYH7):c.3337-3dupC written in paper as g.23889445insG
ClinVar: 42956, https://www.ncbi.nlm.nih.gov/clinvar/variation/42956/
gnomAD: 0.02126, https://gnomad.broadinstitute.org/variant/14-23889445-T-TG
MultipleGeneVariants:
(1) TTN Variant:
Variant: NM_133378.4(TTN):c.29331A>G (p.Glu9777=) written in paper as p.Arg9778Ter, g.179547454
ClinVar: 46884, https://www.ncbi.nlm.nih.gov/clinvar/variation/46884/
gnomAD: 0.005805, https://gnomad.broadinstitute.org/variant/2-179547455-T-C
Supplementary Data: Table S3
Case 35:
DiseaseAssertion: left ventricular noncompaction
CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)
CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1
CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.
CaseGenotypingMethod: WES, variant enrichment analysis
Variant: NM_000257.3(MYH7):c.115G>A (p.Val39Met)
ClinVar: 42827, https://www.ncbi.nlm.nih.gov/clinvar/variation/42827/
gnomAD: 0.00004596, https://gnomad.broadinstitute.org/variant/14-23902827-C-T
Case153: Female, 0.083 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)
HPOsFreeText: Left Ventricular Ejection Fraction at 46%, LVDD-Z score at 0.795
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: Sister also has LVNC
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.1342G>A (p.Glu448Lys)
CAID: CA389050830 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1342G%3EA
gnomAD: Not in gnomAD
Case361: Female, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 38%, LVDD-Z score at 0.977
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.896-1G>A
CAID: CA389051805 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.896-1G%3EA
gnomAD: Not in gnomAD
Case333: Male, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 10%, LVDD-Z score at -0.4
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.668C>T (p.Ala223Val)
CAID: CA389052292 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.668C%3ET
gnomAD: Not in gnomAD
Case250: Male, 0.04 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0001635 (Left ventricular noncompaction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 60%, LVDD-Z score at 1.6326
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.2030A>T (p.Glu677Val)
CAID: CA389049283 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2030A%3ET
gnomAD: Not in gnomAD
Case427: Female, 1.5 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
FamilyInfo: Father has DCM
CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)
HPOsFreeText: Left Ventricular Ejection Fraction at 44.1%, LVDD-Z score at 1.3709
CaseNotHPOs: HP:0011675, HP:0001635 (Arrhythmia, Heart failure)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo:
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.2821C>T (p.Arg941Cys)
CAID: CA389046936 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2821C%3ET
gnomAD: Not in gnomAD
Case392: Male, 0.083 years onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)
HPOsFreeText: Left Ventricular Ejection Fraction at 29%, LVDD-Z score at 2.1428
CaseNotHPOs: HP:0011675 (Arrhythmia)
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo: No family history
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.944A>G (p.Gln315Arg)
CAID: CA389051698 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.944A%3EG
gnomAD: Not in gnomAD
Case378: Female, Birth onset, Japan, Asian
DiseaseAssertion: Left ventricular noncompaction
FamilyInfo: Sister has LVNC
CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635, HP:0005110 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure, Atrial fibrillation)
HPOsFreeText: Left Ventricular Ejection Fraction at 20%, LVDD-Z score at 0.1
CaseNotHPOs: N/A
NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes
CaseAddInfo:
CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.
CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.1859T>C (p.Leu620Pro)
CAID: CA389049669 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1859T%3EC
gnomAD: Not in gnomAD
MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient.
Case1: n/a
DiseaseAssertion: HCM
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
GenotypingMethod: Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened.
Variant: NM_000257.4:c.3158G>A
ClinVar: 155814
CAID: CA013417
gnomAD: https://gnomad.broadinstitute.org/variant/14-23891476-C-T
0.0006368 European - Finnish
MYH7 (3)
Case#: SF No. 28, GC Case No. 21, male, 83
DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy
FamilyInfo: No
CasePresentingHPOs: N/A
CaseHPOFreeText: Gastric cancer,
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: WES, Sanger sequencing,
Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)
ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/
CAID: N/A
gnomAD: absent
MYH7 (3)
Case#: SF No. 30, GC Case No. 23, female, 31
DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy
FamilyInfo: Yes, one affected
CasePresentingHPOs: N/A
CaseHPOFreeText: Gastric cancer,
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: WES, Sanger sequencing,
Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)
ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/
CAID: N/A
gnomAD: absent
KMP 4
Case KMP 4: Eastern Slovakia, Female, 69yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification II-III
CaseNotHPOFreeText: left ventricular outflow tract obstruction
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
KMP 16
Case KMP 16: Eastern Slovakia, Female, 60yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 39-40%, New York Heart Association Classification = I, implantable cardioverter defibrillator
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
KMP 8
Case KMP 8: Eastern Slovakia, Female, 60yo
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo: no family history
CaseHPOFreeText: left ventricular outflow tract obstruction , left ventricular ejection fraction = 55-60%,
CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)
CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing
Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)
ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/
gnomAD: n/a
MultipleGeneVariants:
(1) SCN5A Variant:
Variant: NM_198056.2(SCN5A):c.3784G>A (p.Gly1262Ser)
ClinVar: 9399, https://www.ncbi.nlm.nih.gov/clinvar/variation/9399/
gnomAD: 0.00002828, https://gnomad.broadinstitute.org/variant/3-38607956-C-T
7
Case7: Female, 13 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0001639, HP:0001667, HP:0001279 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Syncope)
HPOsFreeText: 2 SCD risk factors, NYHA class is II, Right ventricular wall thickness 12 mm
CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680, HP:0011675 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease, Arrhythmia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.
Variant reported as below, but no SNP corresponds to the variant.
Variant: NP_000248.2:p.R719E
ClinVar: N/A
gnomAD: N/A
MultipleGeneVariants:
MYOM1 Variant:
Variant: NM_003803.3:c.2507G>T (p.Gly836Val)
CAID: CA8874590 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_003803.3:c.2507G%3ET
gnomAD: East Asian 5.044e-4, Overall 3.707e-5 https://gnomad.broadinstitute.org/variant/18-3129517-C-A
AKAP9 Variant:
Variant: NM_005751.4:c.11590T>C (p.Cys3864Arg)
CAID: CA368165252 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_005751.4:c.11590T%3EC
gnomAD: Not in gnomAD
1
Case1: Male, 27 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
CasePresentingHPOs: HP:0001639, HP:0001667 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy)
HPOsFreeText: 0 SCD risk factors, NYHA class is I, Right ventricular wall thickness 13 mm
CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680, HP:0011675 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease, Arrhythmia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.
Variant listed as MYH7-478N. Typo is suspected, below is the entry for MYH7-I478N, the actual variant at this location
Variant: NM_000257.3:c.1433T>A (p.Ile478Asn)
CAID: CA389050614 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1433T%3EA
gnomAD: Not in gnomAD
MultipleGeneVariants:
TTN Variants:
Unknown Variant
Variant1: TTN-S3872fs
CAID: N/A
gnomAD: N/A
Unknown Variant
Variant2: TTN-S6350A
CAID: N/A
gnomAD: N/A
Unknown Variant
Variant3: TTN-P10663R
CAID: N/A
gnomAD: N/A
ACTN2 Variant
Unknown Variant
Variant: ACTN2-P32fs
CAID: N/A
gnomAD: N/A
Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing
PMID: 32481709
Gene: MYH7
HGNC: 7577
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.2722C>G (p.Leu908Val)
ClinVar: 14097, https://www.ncbi.nlm.nih.gov/clinvar/variation/14097/
gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23893316-G-C
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.428G>A (p.Arg143Gln)
ClinVar: 43006, https://www.ncbi.nlm.nih.gov/clinvar/variation/43006/
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23901922-C-T
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.611G>A (p.Arg204His)
ClinVar: 43095, https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/
gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23900998-C-T
Supplementary Data, Table 2
Variant noted to be present in 3 individuals
Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)
ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: n/a
Table 1 and 4
Case A36: Female, 49yo
DiseaseAssertion: HCM
FamilyInfo: positive family history
CaseHPOFreeText: interventricular septum thickness = 22mm, left ventricular end diastolic diameter = 42.2mm, left ventricular end systolic diameter = 31.7mm, left ventricular posterior wall thickness = 10.9mm, left atrium = 32mm, left ventricular ejection fraction = 54%
CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)
CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing
Variant: NM_000257.3:c.2654A>C
CAID: CA389047874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047874
gnomAD: n/a
Table 1 and 4
Case A12: Female, 21yo
DiseaseAssertion: HCM
FamilyInfo: positive family history
CaseHPOFreeText: interventricular septum thickness = 25.9mm, left ventricular end diastolic diameter = 32.0mm, left ventricular end systolic diameter = 18.4mm, left ventricular posterior wall thickness = 9.4mm, left atrium = 26.9mm, left ventricular ejection fraction = 75%
CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)
CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing
Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)
ClinVar: 14104, https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/
gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A
Supplementary Data Table S3
Case: 210
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_000257.3:c.1021T>C (p.Phe341Leu)
CAID: CA389051533 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051533
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) MYH6 Variant
Variant: NM_002471.3:c.5209A>T (p.Thr1737Ser)
CAID: CA257777730 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257777730
gnomAD: Not in gnomAD
(2) VCL Variant
Variant: NM_014000.2(VCL):c.1907A>G (p.His636Arg)
ClinVar: 45594 https://www.ncbi.nlm.nih.gov/clinvar/variation/45594/
gnomAD: 0.006330, https://gnomad.broadinstitute.org/variant/10-75860740-A-G
Supplementary Data Table S3
Case: 329
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
Variant1: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
Variant2: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)
ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/
gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C
Supplementary Data Table S3
Case: 154
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.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
MultipleGeneVariants:
(1) FBN1 Variant
Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)
ClinVar: 199948 https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/
gnomAD: 0.006608, https://gnomad.broadinstitute.org/variant/15-48782053-A-G
(2) JUP Variant
Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)
ClinVar: 45842 https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/
gnomAD: 0.01341, https://gnomad.broadinstitute.org/variant/17-39913771-C-T
Supplementary Data Table S3
Case: 204
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.3158G>A (p.Arg1053Gln)
ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/
gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T
Supplementary Data Table S3
Case: 145
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
Variant1: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T
Variant2: NM_000257.4(MYH7):c.3853+7C>T
ClinVar: 42977 https://www.ncbi.nlm.nih.gov/clinvar/variation/42977/
gnomAD: 0.003956, https://gnomad.broadinstitute.org/variant/14-23888685-G-A
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
(2) 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
Mutations in the cardiac troponin T gene show various prognoses in Japanese patients with hypertrophic cardiomyopathy
PMID: 23494605
Gene: TNNT2
HGNC ID: 11949
20
Case: Patient 20, female, 39yo, symptom onset in adulthood
CasePresentingHPOs: HP:0002460, HP:0003327, HP:0003701, HP:0003458 (distal muscle weakness, axial muscle weakness, proximal muscle weakness, EMG: myopathic abnormalities)
HPOsFreeText: normal CK levels, cores present on muscle biopsy
CaseNotHPOs: HP:0002650 (scoliosis)
NotHPOsFreeText: no respiratory or cardiac involvement
FamilyInfo: no 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_000257.3:c.5808G>C
CAID: CA389033338, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389033338
gnomAD: absent
CaseMYH7-21: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 1 other proband shares this genotype
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.2389G>A (p.Ala797Thr)
ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894525-C-T
CaseMYH7-34: 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.1370T>C (p.Ile457Thr)
ClinVar: 42840 https://www.ncbi.nlm.nih.gov/clinvar/variation/42840/
gnomAD: European (Non-Finnish) 8.790e-6, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/14-23898201-A-G
CaseMYH7-25: Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: 1 other proband shares this genotype
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.2207T>C (p.Ile736Thr)
ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: Not in gnomAD
CaseMYH7-28: 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.2155C>T (p.Arg719Trp)
ClinVar: 14104 https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/
gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A
CaseMYH7-36: 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.1208G>A (p.Arg403Gln)
ClinVar: 14087 https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/
gnomAD: Not in gnomAD
Phenotypes of hypertrophic cardiomyopathy: genetics, clinics, and modular imaging
PMCID: 32040801
Gene: MYH7
HGNC: 7577
"The purpose of this article is to summarize current data regarding all HCM phenotypes, from genetics to pathogenesis, clinical manifestations, diagnosis, and treatment."
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM 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 one HCM proband
Variant: NM_000257.4(MYH7):c.2332G>A (p.Asp778Asn)
ClinVarID: 181369 https://www.ncbi.nlm.nih.gov/clinvar/variation/181369/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM 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 one proband
Variant: NM_000257.4(MYH7):c.1231G>A (p.Val411Ile)
ClinVarID: 181339 https://www.ncbi.nlm.nih.gov/clinvar/variation/181339/
gnomAD: 0.00005643, http://gnomad.broadinstitute.org/variant/14-23898464-C-T
DiseaseAssertion: None
VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of 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.
Variant: NM_000257.4(MYH7):c.2360G>A (p.Arg787His)
ClinVar: 42900 https://www.ncbi.nlm.nih.gov/clinvar/variation/42900/
gnomAD: 0.001339, http://gnomad.broadinstitute.org/variant/14-23894554-C-T
DiseaseAssertion: 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, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were all tested in the PanCM panel.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 305 PanCM 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 one PanCM proband
Variant: NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys)
ClinVar: 14092 https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/
gnomAD: Not in gnomAD
DiseaseAssertion: Hypertrophic Cardiomyopathy
VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.
VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM 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 HCM probands
Variant: NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)
ClinVarID: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/
gnomAD: Not in gnomAD
We obtained induced pluripotent stem cells (iPSCs) from the HCM patient carrying heterozygous p.M659I (c.1977G > A) mutation in MYH7 encoding for β-myosin heavy chain (See Table 1). The mutation was also found in a population study of HCM patients (Richard et al., 2003) but its clinical significance is still unknown.
Case1: male, 38, caucasian
DiseaseAssertion: hypertrophic cardiomyopathy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:
GenotypingMethod: the presence of p.M659I (c.1977G > A) mutation in the iPSC lines was confirmed by Sanger sequencing of exon 18 of MYH7 (Fig. 1F).
Variant: NM_000257.4:c.1977G>A
ClinVar: not found
CAID: CA389049400
gnomAD: not found
MYH7 R663H (n = 2)
Case: HCM mutation carrier
DiseaseAssertion: Hypertrophic cardiomyopathy
CasePresentingHPOs: n/a
CasePreviousTesting: n/a
CaseGenotypingMethod: n/a
Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His), variant noted to be in 2 individuals utilized in this study
ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T
Case 1 (the Proband)
Case1: 3 year old female
DiseaseAssertion: LVNC
FamilyInfo: sister and brother diagnosed with Ebstein's anomaly, LVNC, and VSD, and same novel mutation was identified in sister, brother, and father
CasePresentingHPOs: HP:0031664, HP:0010316, HP:0001631, HP:0002789, HP:0001649, HP:0001680
"Systolic heart murmur, Ebstein anomaly of the tricuspid valve, Atrial septal defect, Tachypnea, Tachycardia, Coarctation of aorta
CaseHPOFreeText: precordial systolic murmur at 4 days old, moderate tricuspid valve insufficiency, right heart enlargment, membranous VSD, feeding poorly at 11 days
CasePreviousTesting: No mutations were identified in the TAZ, LMNA/C, MYBPC3, TNNT2, TNNI3, ACTC, and TPM1 genes
GenotypingMethod: Sequence analysis of MYH7
Variant: NM_000257.4:c.1085T>G
ClinVar: not found
CAID: CA389051391
gnomAD: not found
Supplementary Data: S2 Table
Case 103: Spanish, 24yo, 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, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2389G>A (p.Ala797Thr)
ClinVar: 42901, https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894525-C-T
MultipleGeneVariants:
(1) TTN Variants:
Variant1: NM_001256850.1(TTN):c.28363G>A (p.Val9455Met)
ClinVar: 202551, https://www.ncbi.nlm.nih.gov/clinvar/variation/202551/
gnomAD: 0.00005702, https://gnomad.broadinstitute.org/variant/2-179571287-C-T
Variant2: NM_133378.4:c.19943T>G
CAID: CA2000580, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.19943T%3EG
gnomAD: 0.00001635, https://gnomad.broadinstitute.org/variant/2-179584544-A-C
Variant3: NM_133378.4(TTN):c.77273G>A (p.Arg25758Gln)
ClinVar: 47442, https://www.ncbi.nlm.nih.gov/clinvar/variation/47442/
gnomAD: 0.0002431, https://gnomad.broadinstitute.org/variant/2-179425882-C-T
Supplementary Data: S2 Table
Case 13: Spanish, 21yo, 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:c.920C>G
CAID: CA389051750, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051750
gnomAD: n/a
Supplementary Data: S2 Table
Case 135: Spanish, 50yo, 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, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.958G>A (p.Val320Met)
ClinVar: 161328, https://www.ncbi.nlm.nih.gov/clinvar/variation/161328/
gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23899810-C-T
Supplementary Data: S2 Table
Case 39: Spanish, 33yo, 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, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3:c.1168C>G
CAID: CA389051200, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051200
gnomAD: n/a
Supplementary Data: S2 Table
Case 193: Spanish, 47yo, 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, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2389G>A (p.Ala797Thr)
ClinVar: 42901, https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894525-C-T
Supplementary Data: S2 Table
Case 121: Spanish, 23yo, 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, Next-gen sequencing panels of 55 or 78 genes
Variant: NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg)
ClinVar: 14098, https://www.ncbi.nlm.nih.gov/clinvar/variation/14098/
gnomAD: n/a
MultipleGeneVariants:
(1) TTN Variants:
Variant1: NM_133378.4(TTN):c.52301A>G
ClinVar: 47157, https://www.ncbi.nlm.nih.gov/clinvar/variation/47157/
gnomAD: 0.0005511, https://gnomad.broadinstitute.org/variant/2-179456541-T-C
Variant2: NM_133378.4:c.50516C>G
CAID: CA349508241, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.50516C%3EG
gnomAD: n/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.1988G>A (p.Arg663His)
ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T
Supplementary Data table 1
Variant noted to be present in 3 individuals
Variant: NM_000257.3(MYH7):c.976G>C (p.Ala326Pro)
ClinVar: 43117, https://www.ncbi.nlm.nih.gov/clinvar/variation/43117/
gnomAD: 0.00008846, https://gnomad.broadinstitute.org/variant/14-23899792-C-G
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:c.3100-2A>C
CAID: CA035633, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA035633
gnomAD: 0.00002475, https://gnomad.broadinstitute.org/variant/14-23891536-T-G
Pedigree 2
Case: Pedigree 2 proband, male, 37yo at diagnosis, Iraqi‐Jewish
CasePresentingHPOs: HP:0001639, HP:0005110, HP:0001708, HP:0005180 (hypertrophic cardiomyopathy, atrial fibrillation, right heart failure, tricuspid regurgitation)
HPOsFreeText: clinical severity: moderate to asymptomatic
CaseNotHPOs:
NotHPOsFreeText: skeletal involvement
CasePreviousTesting: exact genes sequenced not specified
CaseGenotypingMethod: Fifty‐six genes known to cause HCM were sequenced in parallel
Variant: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)
ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/
gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A
FamilyInfo: older brother had sudden death at 33yo with postmortem diagnosis of HCM, patient's siblings, aged 67 and 70, were also found to be heterozygous for this variant, though they are both clinically asymptomatic with no echocardiographic evidence of HCM
7
Case#: 7
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: HP:0032092, HP:0031656, HP:0004756 (LV outflow tract obstruction, systolic anterior motion of the mitral valve, ventricular tachycardia)
CaseHPOFReeText: preserved ejection fraction (EF >60%)
Variant: NM_000257.4:c.1432A>G
ClinVar: 181347 https://www.ncbi.nlm.nih.gov/clinvar/variation/181347/
CAID: PA296828
gnomAD: not found
6
Case#: 6
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: HP:0032092, HP:0031656, HP:0025168 (LV outflow tract obstruction, systolic anterior motion of the mitral valve, diastolic dysfunction)
CaseHPOFReeText: preserved ejection fraction (EF >60%)
Variant: NM_000257.3:c.1988G>A
ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/
CAID: PA097667
gnomAD: 0.00003097 European (Non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T
MicroRNA-214 provokes cardiac hypertrophy via repression of EZH2
PMID: 23727574
Gene: MYH7
HGNC: 7577
Poor Prognosis of Rare Sarcomeric Gene Variants in Patients with Dilated Cardiomyopathy
PMID: 24119082
Gene: MYH7
HGNC: 7577
24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2, and 13 in TTN) affecting 52 subjects in 25 families:
MYH7 (c.2945 T>C, p.M982T; c.4300 C>T, p.R1434C; c.4498 C>T, p.R1500W)
One patient had reduced LVEF: a 44-year-old man, diagnosed with CM and a MYH7-mutation (c.5401G > A) at the age of 36 years. At age 44 years, he was diagnosed with dilated cardiomyopathy (DCM), LVIDD 74 mm, severe heart failure (LVEF 29%) and had an ICD implantation for primary prevention. The patient was later hospitalized for pulmonary oedema and is currently (age 48 years) awaiting a heart transplantation. There has been no anti-tachycardia pacing or shock therapy from the ICD.
Case: male, 44yo at diagnosis
DiseaseAssertion: Dilated cardiomyopathy (DCM)
CasePresentingHPOs: HP:0012664, HP:0001635, HP:0100598, HP:0001324, HP:0003388 (reduced ejection fraction, heart failure, pulmonary oedema, muscle weakness, fatigability)
HPOsFreeText: reduced LVEF (=29%), diagnosed with congenital myopathy at 36yo, LVIDD = 74mm, creatine kinase < 600 U/l, ICD implantation, waiting heart transplantation at 48yo
CaseNotHPOs:
NotHPOsFreeText: anti-tachycardia pacing or shock therapy from the ICD
CasePreviousTesting: ACTA1, BIN1, DNM2, MYH7, MTM1, NEB, RYR1, SCN4A, SEPN1, TPM2, TPM3
CaseGenotypingMethod: PCR amplification of exons of genes investigated and Sanger sequencing or NGS
Variant: NM_000257.4(MYH7):c.5401G>A (p.Glu1801Lys)
ClinVar: 43069, https://www.ncbi.nlm.nih.gov/clinvar/variation/43069/
gnomAD: absent
HCM506
Case#: HCM506, male, 19 yr, smoker
DiseaseAssertion: HCM
FamilyInfo: None
CasePresentingHPOs: 48mm LAD, 20mm LVST, 43mm LVEDD, 75% LVEF, 21mm Maxi LVWT, 59mmHg Maxi LVOTG, 104464396 raw RNA-seq reads, 98442104 HQ reads (94.24%), 96.88% mapping rate, 721500 total variant, 33453 exonic variant
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,
Variant: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)
ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/
CAID: N/A
gnomAD: 0.00001548 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T
HCM957
Case#: HCM957, male, 30 years,
DiseaseAssertion: HCM
FamilyInfo: Yes, no other HCM in family
CasePresentingHPOs: syncope (HP:0001279)
CaseHPOFreeText: inverted T-waves, ST-segment depression, left anterior branch block, 28mm MLVWT, 58% LVE F, 1.25 E/A ratio, LVOT-PG 7mm
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: sequencing, physical examination, ECG, 3D modeling, statistical analysis
MultipleGeneVariants:
(1) Variant: NM_000257.4(MYH7):c.2360G>A (p.Arg787His)
ClinVar: 42900 https://www.ncbi.nlm.nih.gov/clinvar/variation/42900/
CAID: N/A
gnomAD: 0.001339 South Asian https://gnomad.broadinstitute.org/variant/14-23894554-C-T
(2) Variant: NM_000257.4(MYH7):c.5561C>T (p.Thr1854Met)
ClinVar: 161320 https://www.ncbi.nlm.nih.gov/clinvar/variation/161320/
CAID: N/A
gnomAD: 0.00005423 European (Non-Finnish) https://gnomad.broadinstitute.org/variant/14-23883310-G-A
HCM275
Case#: HCM275, male, 59 years, I-1
DiseaseAssertion: HCM
FamilyInfo: Yes, daughter has HCM
CasePresentingHPOs: syncope (HP:0001279)
CaseHPOFreeText: inverted T-waves, ST-segment depression, 28mm MLVWT, 65% LVE F, 1.3 E/A ratio, LVOT-PG 68mm
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseGenotypingMethod: sequencing, physical examination, ECG, 3D modeling, statistical analysis
MultipleGeneVariants:
(1) Variant: NM_000257.4(MYH7):c.2081G>A (p.Arg694His)
ClinVar: 264068 https://www.ncbi.nlm.nih.gov/clinvar/variation/264068/
CAID: N/A
gnomAD: 0.00004008 African/African-American https://gnomad.broadinstitute.org/variant/14-23895254-C-T
(2) Variant: NM_000257.4(MYH7):c.4985G>A (p.Arg1662His)
ClinVar: 43049 https://www.ncbi.nlm.nih.gov/clinvar/variation/43049/
CAID: N/A
gnomAD: 0.0002894 Ashkenazi Jewish https://gnomad.broadinstitute.org/variant/14-23885010-C-T
Supplementary Data: Online Table 2a
Case:
CasePresentingHPOs: HP:0001642 (pulmonary stenosis)
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.1325G>A (p.Arg442His)
ClinVar: 181342, https://www.ncbi.nlm.nih.gov/clinvar/variation/181342/
gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23898246-C-T
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:c.1245_1247dup
CAID: CA913184873, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184873
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:c.5773C>G
CAID: CA257807342, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257807342
gnomAD: n/a
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:c.4048_4050del
CAID: CA913184874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184874
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:c.2085_2097dup
CAID: CA704294509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2085_2097dup
gnomAD: n/a
CaseMYH7-8: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.427C>T (p.Arg143Trp)
ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/
gnomAD: East Asian 1.087e-4, Overall 2.784e-5 https://gnomad.broadinstitute.org/variant/14-23901923-G-A
CaseMYH7-16: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2681A>G (p.Glu894Gly)
ClinVar: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/
gnomAD: Not in gnomAD
CaseMYH7-22: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2788G>A (p.Glu930Lys)
ClinVar: 42933 https://www.ncbi.nlm.nih.gov/clinvar/variation/42933/
gnomAD: Not in gnomAD
CaseMYH7-26: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.2609G>A (p.Arg870His)
ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/
gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.072e-6 https://gnomad.broadinstitute.org/variant/14-23894048-C-T
CaseMYH7-1: N/A
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.
Variant: NM_000257.3:c.1987C>T (p.Arg663Cys)
ClinVar: 42874 https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/
gnomAD: Not in gnomAD
Trip12, a HECT domain E3 ubiquitin ligase, targets Sox6 for proteasomal degradation and affects fiber type-specific gene expression in muscle cells
PMID: 23663701
Gene: MYH7
HGNC: 7577
Supplementary Data: Table 2
Case O:
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
MultipleGeneVariants:
(1) BAG3 Variant:
Variant: NM_004281.3:c.1090G>A
CAID: CA214224881, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA214224881
gnomAD: n/a
Supplementary Data: Table 2
Case 1:
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: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)
Variant 1 - maternal: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)
ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/
gnomAD: n/a
Variant 2 - paternal: NM_000257.3:c.328G>A
CAID: CA036654, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA036654
gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23902310-C-T
MultipleGeneVariants:
(1) FHL1 Variant:
Variant (maternal): NM_001159702.2:c.968C>T
CAID: CA10525127, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA10525127
gnomAD: 0.000005449, https://gnomad.broadinstitute.org/variant/X-135292109-C-T
(2) SYNE1 Variant:
Variant (maternal): NM_033071.3(SYNE1):c.18514G>A (p.Glu6172Lys)
ClinVar: 199251, https://www.ncbi.nlm.nih.gov/clinvar/variation/199251/
gnomAD: 0.00003536, https://gnomad.broadinstitute.org/variant/6-152589279-C-T
Table 5
Case LO4: Italian
DiseaseAssertion: HCM (late-onset)
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:c.3367G>C
CAID: CA389044118, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389044118
gnomAD: n/a
A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias
PMID: 28491642
Gene: ACTC1
HGNC ID 143
A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias
A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias PMID: 28491642
Gene: ACTC1
HGNC ID: 143
A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias
PMID: 28491642
Gene: ACTC1
HGNC ID: 143
HCM003
CaseHCM003: 31 yrs report, Vietnam, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0002875, HP:0031295, HP:0006698, HP:0001705 (Exertional dyspnea, Left atrial enlargement, Dilatation of the ventricular cavity, Right ventricular outlet obstruction)
HPOsFreeText: Maximal LV thickness 29 mm
CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy
CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.
Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)
ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/
gnomAD: Not in gnomAD
CaseCM1839: Female, 12 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2221G>T (p.Gly741Trp)
ClinVar: 177665 https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/
gnomAD: Not in gnomAD
MultipleGeneVariants:
(1) BAG3 Variant Variant: NM_004281.3:c.1015A>G (p.Ile339Val)
ClinVar: 228453 https://www.ncbi.nlm.nih.gov/clinvar/variation/228453/
gnomAD: East Asian 5.437e-5, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/10-121436081-A-G
CaseCM1871: Male, 0 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother shows negative for this variant with no symptoms
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.2608C>T (p.Arg870Cys)
ClinVar: 161326 https://www.ncbi.nlm.nih.gov/clinvar/variation/161326/
gnomAD: Ashkenazi Jewish 9.923e-5, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894049-G-A
CaseCM1844: Male, 6 years diagnosis, Japan, Asian
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)
NotHPOsFreeText: Neuromuscular disease, Malformation syndromes
CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother and father are both negative for this variant
CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.
CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.
Variant: NM_000257.3:c.1357C>T (p.Arg453Cys)
ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: Not in gnomAD
D
FamilyD
DiseaseAssertion: Left ventricular noncompaction (LVNC)
FamilyInfo: Presenting LVNC, Identified rare, protein changing mutations in MYH7, none of which have been previously reported but all of which were predicted to be pathogenic with multiple in silico prediction algorithms
GenotypingMethod: Whole exome sequencing analysis
Variant: NM_000257.4:c.488A>C
ClinVar: not found
CAID: CA389052716
gnomAD: not found
Deep basal inferoseptal crypts occur more commonly in patients with hypertrophic cardiomyopathy due to disease-causing myofilament mutations
PMID: 23771913
Gene: MYH7
HGNC: 7577
"Deep basal inferoseptal crypts occur more commonly in patients with HCM with disease-causing mutations than in those with genotype-negative HCM."
21
CaseVI: Brazil, Caucasian
DiseaseAssertion: Hypertrophic cardiomyopathy
FamilyInfo: Family history of HCM
CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.
CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.
Variant: NM_000257.3:c.2389G>A (p.Ala797Thr)
ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/
gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894525-C-T
HCM1.1
CaseHCM1.1: Indian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0000819 (Diabetes mellitus)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.611G>A (p.Arg204His)
ClinVar: 43095 https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/
gnomAD: East Asian 5.012e-5, Overall 1.767e-5 https://gnomad.broadinstitute.org/variant/14-23900998-C-T
HCM34.1
CaseHCM34.1: Mixed ancestry
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0000819 (Diabetes mellitus)
NotHPOsFreeText: N/A
CaseAddInfo: N/A
CasePreviousTesting: See Table 1
CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.
Variant: NM_000257.3:c.1357C>T (p.Arg453Cys)
ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/
gnomAD: Not in gnomAD
CM007
CaseCM007
DiseaseAssertion: DCM
GenotypingMethod: NGS
MultipleGeneVariants:
VariantMYH7: NM_000257.4:c.2645A>G
ClinVar: not found
CAID: CA389047904
gnomAD: not found
VariantRBM20: NM_001134363.3:c.2062C>T
ClinVar: 202065
CAID: CA335555
gnomAD: https://gnomad.broadinstitute.org/variant/10-112572217-C-T?dataset=gnomad_r2_1
0.00006494 European (non Finnish)
III-3
Case III-3: Female, 6yo
DiseaseAssertion: Left ventricular hypertrophy
CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)
CaseHPOFreeText: double-chambered left ventricle, asymptomatic, normal thickness of septum and left ventricle, left ventricle ventricle end-diastolic diameter = 53.5mm, left ventricular ejection fraction = 64%
CasePreviousTesting: same as proband
CaseGenotypingMethod: Affymetrix Cytoscan 750K Array to check potential candidate copy number variations, segregation analysis using the results from Sanger sequencing
Variant: NM_000257.3:c.998A>T
CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586
gnomAD: n/a
Advanced Single-Cell Mapping Reveals that in hESC Cardiomyocytes Contraction Kinetics and Action Potential Are Independent of Myosin Isoform
PMID: 32302556
Gene: MYH7
HGNC: 7577
This study concludes that "in hESC-CMs the expression of genes associated with electrical activity, contraction, calcium handling, and MyHCs is independently regulated."
Fetal Dilated Cardiomyopathy Associated With Variants of Uncertain Significance in MYH7 and DSG2 Genes: A Case Report and Review of the Literature
PMID: 32171501
Gene: MYH7, DSG2
HGNC: 7577, 3049
CasePT-38: United States
CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)
NotHPOsFreeText: N/A
CaseAddInfo: Two other siblings have the same genotype
CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.
Variant: NM_000257.3:c.727C>T (p.Arg243Cys)
ClinVar: 43101 https://www.ncbi.nlm.nih.gov/clinvar/variation/43101/
gnomAD: European (Non-Finnish) 6.482e-5, Overall 3.184e-5 https://gnomad.broadinstitute.org/variant/14-23900799-G-A
Family B, II:1
CaseBII-1: Male, 23 years diagnosis, China, Asian
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: No family history, pedigree provided
CasePresentingHPOs: HP:0001639, HP:0100749 (Hypertrophic cardiomyopathy, Chest pain)
HPOsFreeText: Interventricular septal thickness at 15.6 mm, Left ventricular posterior wall thickness at 12.1 mm
CaseNotHPOs: N/A
NotHPOsFreeText: N/A
CaseAddInfo: Parents tested negative for variant, therefore it is asserted as de novo
CasePreviousTesting: See list of sequenced genes
CaseGenotypingMethod: Genomic DNA was isolated from whole blood of all patients and controls. Whole coding exons and exon-intron boundaries of the 19 HCM-related genes listed above were amplified and sequenced on Ion Torrent PGM. These variants were then filtered for pathogenicity and compared to the controls. Any mutations found were confirmed by conventional dideoxy sequencing and Sanger sequencing.
Variant: NM_000257.3:c.2572C>T (p.Arg858Cys)
ClinVar: 164324 https://www.ncbi.nlm.nih.gov/clinvar/variation/164324/
gnomAD: Not in gnomAD
AJV
CaseAJV: 17 years diagnosis, Australia
DiseaseAssertion: Hypertrophic Cardiomyopathy
FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.
CasePresentingHPOs: HP:0001639, HP:0006536
(Hypertrophic cardiomyopathy, Obstructive lung disease)
HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,
CaseNotHPOs: N/A
NotHPOsFreeText: 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.1954A>G (p.Arg652Gly)
ClinVarID:177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/
gnomAD: Not in gnomAD
Multiple Gene Variants:
MYBPC3 Variant
Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)
ClinVarID:180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/
gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A
2. Case report
CaseIII/2: 70 year old Caucasian female
DiseaseAssertion: spinal muscular atrophy (SMA),
FamilyInfo: family history was indicative of an autosomal dominant neuromuscular disorder in at least five generations
CasePresentingHPOs: HP:0002076, HP:0003393, HP:0007149, HP:0000365
"Migraine, Thenar muscle atrophy, Distal upper limb amyotrophy, Hearing impairment"
CaseHPOFreeText: impaired mobility of the thumb at age 49 y followed by weakness of the other fingers, mild foot drop bilaterally, recurrent, spontaneous, short-lived aching of the shoulder girdle muscles, reduced tendon reflexes on the upper limbs, weak head anteflexion, recurrent anginal chest pain, reduced Achilles tendon reflexes, and diffuse wasting of all limbs
GenotypingMethod: "DNA analysis"
Variant: NM_000257.4:c.5566G>A
ClinVar: 190403
CAID: CA347253
gnomAD: https://gnomad.broadinstitute.org/variant/14-23883305-C-T
0.000008795 European (non-Finnish)
At 21 h post-transfection, the EGFP-tagged MyHC-slow was distributed throughout the cytoplasm, aggregating into discrete structures. The wild-type aggregates formed long, filamentous structures (Fig. 6A, B). The Arg1712Trp mutant MyHC-slow instead formed many small, round inclusions (Fig. 6C).
ExperimentalAssay
Variant: NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp), homozygous
ClinVar: 14118, https://www.ncbi.nlm.nih.gov/clinvar/variation/14118/
CaseST4-91: Sweden
DiseaseAssertion: Idiopathic Dilated Cardiomyopathy
FamilyInfo: N/A
CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy)
HPOsFreeText: N/A
CaseNotHPOs: HP:0002140, HP:0000822, HP:0001654, HP:0030955, HP:0000819, HP:0002666, HP:0000845, HP:0000820 (Ischemic stroke, Hypertension, Valvular heart disease, Alcoholism, Diabetes mellitus, Pheochromocytoma, Acromegaly, Thyroid disease)
NotHPOsFreeText: Patients were excluded for significant systemic infection, systemic diseases, previous cancer treatment including irradiation, and tachycardia-induced cardiomyopathy or other primary cardiomyopathy.
CaseAddInfo: N/A
CasePreviousTesting: See Supplemental Table 1
CaseGenotypingMethod: Genomic DNA was extracted from the patients. 41 exons of previously-reported genes that were reported in DCM patients were amplified and directly sequenced. Afterwards, the variants were aligned and sorted for pathogenicity.
Variant: NM_000257.3:c.1113G>C (p.Glu371Asp)
CAID: CA389051328 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1113G%3EC
gnomAD: Not in gnomAD