Case#: Male, first evaluated at 3.5 years, diagnostic studies described in paper at age 4.5 years, at time of report 11 years

DiseaseAssertion: Mucopolysaccharidosis Type I and Type II

FamilyInfo:Clinically normal sister, mother and father; parents denied consanguinity; extensive histocompatibility typing of all family members confirmed relationships and did not suggest consanguinity; Maternal uncle died at 11 years having "coarse facial features" but not diagnostic testing. Pedigree, Figure 7, page 82.

CasePresentingHPOs: HP:0000943 (dysostosis multiplex); HP:0000280 (course facial features)

CaseHPOFreeText: at 3.5 years "...gross motor delay, mild expressive language delay, and progressive changes in facial features and joints...noted to be a noisy breather and have a history of frequent ear infections...prominent metopic suture and facial features were said to be coarsened" Height 50th%, weight 95th%, head circumference >98th%. At 11 years of age reported to show progressive intellectual deterioration.

CaseNotHPOs:

CaseEnzymeAssay: Table 2 (page 79): leukocyte IDUA (alpha-L) activity absent (<1.0 nmol/mg/h), plasma IDUA alpha-L <0.20 MU/ml/h); plasma IDS activity was undetectable (0.0 U/mg/h)

CaseUrineAssay:Not reported

CaseERT:Don't know

CaseBMT:Don't know

Variant1:IDUA W402X

Variant1ClinVarID:11908

Variant1CAID:

Variant2: IDUA A300T

Variant2ClinVarID: 11923

Variant2CAID:

AdditionalVariants: IDS R468W (missense 1402C-->T), ClinVarID: 10497

ParentalGenoype:Mother, IDUA A300T and IDS R468W; Father, IDUA W402X

PreviouslyPublished:

PMID: 8554071

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 2 (see Table 1), 1 year and 3 months - deceased (age at report), 1 month and a half (age at onset), male, height of 71 cm, weight of 12 kg, located in the Sfax: Industrial region.

DiseaseAssertion: MPS1 - severe

FamilyInfo: Two affected siblings (Patients 1 and Patient 3), three other familial relations (deceased), parents were 3rd cousins (see Table 2) aged 38 yrs (M) and 40 yrs (F).

CasePresentingHPOs: HP:0000280, HP:0002194, HP:0000238, HP:0000365, HP:0000023 (Coarse facial features, developmental delay, hydrocephaly, hearing impairment, inguinal hernia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: (p.F602X)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: (p.F602X)

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3 (see Table 1), female, 9 months (age at report and onset), height of 51 cm, weight of 19 kg, location at Sfax: Industrial region.

DiseaseAssertion: MPS1 - severe

FamilyInfo: Two affected siblings (Patients 1 and Patient 2), three other familial relations (deceased), parents were 3rd cousins (see Table 2) aged 38 yrs (M) and 40 yrs (F).

CasePresentingHPOs: HP:0001999, HP:0002652 (Abnormal facial shape, skeletal dysplasia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: (p.F602X)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: (p.F602X)

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1 (see Table 1), 5 years and 6 months - deceased (age at report), 2 months (age of onset), male, height of 103 cm, weight of 13 kg, located in the Sfax: Industrial region.

DiseaseAssertion: MPS1 - severe

FamilyInfo: Two affected siblings (Patients 2 and Patient 3), three other familial relations (deceased), parents were 3rd cousins (see Table 2) aged 38 yrs (M) and 40 yrs (F).

CasePresentingHPOs: HP:0000023, HP:0000280, HP:0000365, HP:0000389 (Inguinal hernia, coarse facial feature, hearing impairment, chronic otitis)

CaseHPOFreeText: Pulmonary and cardiac deficiency

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: (p.F602X)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: (p.F602X)

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 21394825

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 12, Female, 0.9 years (diagnosed), 10.1 years (report), 26 kg (weight), 108 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 1.01 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 7.4 (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

Case#: 2, Male, 0.9 years (diagnosed), 4.2 years (report), 11 kg (weight), 65 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0000943, HP:0001387 (Multiple Dysostosis, Joint Stiffness)

CaseHPOFreeText: HM/HSM,

CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: NM/HSM, Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 7.06 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 14.22 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.S157P

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 19, Male, 0.5 years (diagnosed), 2.2 years (report), 8.0 kg (weight), 7.6 cm (height), Iranian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0100790 (Mental Retardation, Facial Dysmorphic Features, Hernia)

CaseHPOFreeText: HM/HSM

CaseNotHPOs: HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 3.72 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 8.4 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.S157P

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 5, Female, 1.2 years (diagnosed), 10.5 years (report), 10.5 kg (weight), 87 cm (height), Iranian

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0100790, HP:0000365, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia, Deafness, Hydrocephalus)

CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea, Cardiac Manifestations (Mitral stenosis/ Aortic insufficiency)

CaseNotHPOs: HP:0007957 (Corneal Opacity)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.69 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 14.80 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.D257G

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

PMID: 30442156 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive

Case#: Patient 2, female, 6 years (age at presentation)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, dysostosis multiplex, hepatomegaly, joint contractures, splenomegaly (HP:0007957, HP:0000943, HP:0002240, HP:0100790, 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.223G>C (p.A75P)

Variant1ClinVarID: N/A

Variant1CAID: CA355946364

Variant2: c.223G>C (p.A75P)

Variant2ClinVarID: N/A

Variant2CAID: CA355946364

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, female, 2 years (age at presentation)

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family not present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, intellectual disability (HP:0007957, HP:0000256, HP:0000943, HP:0010864)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>G (p.M1?)

Variant1ClinVarID: 1323098

Variant1CAID: CA355945206

Variant2: c.1A>G (p.1M?)

Variant2ClinVarID: 1323098

Variant2CAID: CA355945206

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID:20553232

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: OS of sibship 9, female, 7 years old (age at diagnosis), 14 years old (age at ERT enrollment), 7 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected YS (YS of sibship 9)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contracture)

CaseHPOFreeText: Cardiac disease, ocular, respiratory, and musculoskeletal involvement.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - At T2, ocular and cardiac symptoms progressed from mild to moderate/severe. In addition, pulmonary function worsened, and contractures and lower extremity weakness progressed. Had stabilization of dysostosis multiplex and no progression of motor function delays.

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: YS of sibship 8, male, 3.3 years old (age at diagnosis), 3.7 years old (age at ERT enrollment), 5.8 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected OS (OS of sibship 8)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contracture)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Had progression of cardiac symptoms at T2, dysostosis multiplex stabilized, and remained milder. Joint contractures progressed into the moderate range.

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS2 of sibship 6 (see Table 1), male, 8 years old (age at diagnosis), 11 years old (age at ERT enrollment), 6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Two affected siblings (OS1 and YS of sibship 6)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828 (Corneal opacity, dysostosis, joint contractures)

CaseHPOFreeText: Cardiac disease, musculoskeletal symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Pulmonary function was 45–50 % of normal at T2. No restrictions in ADL.

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 5 (Thai, male, diagnosed age 7y)

DiseaseAssertion: MPS1

FamilyInfo: Thai, no consanguinity

CasePresentingHPOs: 0007759 (cloudy cornea); 0034337 (claw hand): 0002240 (hepatomegaly); 0001387 (multiple joint stiffness); 0000280 (coarse facies); 0000365 (hearing impairment)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: no neurological symptoms detected

CaseEnzymeAssay: 3.27 nmole/18 h/mg protein

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:IDUA c.1138C>T (p.Q380X)

Variant1ClinVarID:

Variant1CAID:

Variant2: IDUA c.*1T>C Ex14 (p.X654Rext38)

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 4 (Thai, female, diagnosed at 4y6m)

DiseaseAssertion: MPS1

FamilyInfo: Thai, no consanguinity

CasePresentingHPOs: 0007759 (cloudy cornea); 0002240 (hepatomegaly); 0002857 (knock knee)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: no neurological symptoms detected

CaseEnzymeAssay: 3.23 nmole/18 h/mg protein

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:IDUA c.935G>A: Ex7 (p.W312X)

Variant1ClinVarID: 8555322

Variant1CAID:

Variant2: IDUA c.*1T>C Ex14 (p.X654Rext38)

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 3 (Thai, male, diagnosed at age 3y8m)

DiseaseAssertion: MPS1

FamilyInfo: Thai, no consanguinity

CasePresentingHPOs: 0007759 (cloudy cornea), 0034337 (claw hand), 0002240 (hepatomegaly)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: no neurological symptoms detected

CaseEnzymeAssay: not determined

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:IDUA c.265G>A (p.R89Q)

Variant1ClinVarID: 11922

Variant1CAID:

Variant2: IDUA c.*1T>C: Ex14 (p.X654Rext38)

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 2 (Thai, male, diagnosed at 9years 6months)

DiseaseAssertion: MPS1

FamilyInfo: Thai, Parental consanguinity (relationship not defined)

CasePresentingHPOs: 0007759 (cloudy cornea); 0034337 (claw hand); 0002240 (hepatomegaly)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: no neurological symptoms noted

CaseEnzymeAssay: 3.03 nmole/18 h/mg protein

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:IDUA c;*1T>C: Ex14 (p.X654Rext38)

Variant1ClinVarID:

Variant1CAID:

Variant2: *IDUA c;1T>C: Ex14 (p.X654Rext38)

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 8 year-old Chinese Han boy. At age 3 years physical disabilities began appearing.

DiseaseAssertion: Mucopolysaccharidosis type I, MPS-I

FamilyInfo: Proband is the third child of healthy non-consanguineous parents. Paper states there is "no family history of related genetic diseases." Figure 1 has a pedigree of proband's family.

CasePresentingHPOs: HP:0000280 (coarse facial features), HP:0000256 (macrocephaly), HP:0007957 (corneal clouding), HP:0000158 (macroglossia), HP:0004322 (short stature), HP:0000470 (short neck), HP:0001537 (umbilical hernia), HP:0034392 (joint contracture), HP:0011369 (large Mongolian spot on the back skin), HP:0040079 (irregular teeth), HP:0002240 (hepatomegaly), HP:0034337 (claw hand deformity),

CaseHPOFreeText: Dorsal kyphosis; extreme myopia found via optical examination (visual acuity reached 0.4 in right eye and 0.5 in left eye); thickening of heart valves, mild tricuspid, and aortic valve regurgitation found via Color Doppler ultrasonography; normal intelligence indicated with Wechsler Preschool and Primary Scale of Intelligence scale; cone-shaped phalanges; bilateral coxa vara; small epiphyses on the distal femur and proximal-distal tibiofibula; thin bone cortex; short femoral shaft; multiple diffuse abnormal signals in the bilateral frontal-parietal lobes and left part of the corpus callosum; proband was born at a 3.35 kg weight and 51 cm height

CaseNotHPOs:

CaseNotHPOFreeText: No prominent abnormalities found in blood thyroid hormone levels

CaseEnzymeAssay: "alpha-L-iduronidase activity was significantly decreased in the patient leukocytes (0.65 nmol/h/mg protein)"

CaseUrineGAGs: No urine GAG levels reported for this proband

CaseERT: Don't know

CaseBMT: Don't know

Variant1: c.159‐9T>A

Variant1ClinVarID:

Variant1CAID: CA3044589050

Variant2: c.159‐9T>A

Variant2ClinVarID:

Variant2CAID: CA3044589050

AdditionalVariants: No other pathogenic variants were found/were associated with clinical features

ParentalGenotype: Proband's father is heterozygous for c.159‐9T>A IDUA mutation. DNA from mother and sister of proband showed wild-type allele. Paper states that proband's MPS-I is "caused by UPD(4)pat leading to homozygosity for one pathogenic splicing variant. . ."

PreviouslyPublished: No mention of previous publication

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Pt 5, age is 11 months (proband can be found in Table 1)

DiseaseAssertion: Hurler syndrome, mucopolysaccharidosis type IH, MPS IH, MPS type I

FamilyInfo: No family information provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: In methods it is stated that an IDUA activity assay was conducted on cartilaginous pellets generated from patient-derived bone marrow stromal cells at 5 weeks. However, results of the IDUA activity assays are not stated.

CaseUrineGAGs: "Significantly higher levels of GAGs in MPS IH compared with HD pellets at.1 week of chondrogenic differentiation, thus indicating that GAG accumulation in MPS IH can be seen during cell condensation and early differentiation stages." Total GAG content for each sample in ug GAG/ug DNA shown in Figure 4 graphs.

CaseERT: Don't know

CaseBMT: Don't know

Variant1: p.W402X

Variant1ClinVarID:

Variant1CAID: PA3051368272

Variant2: p.W402X

Variant2ClinVarID:

Variant2CAID: PA3051368272

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental information provided

PreviouslyPublished: No mention of being previously published

PMID: 28676128

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 17 (group 2), Poland, female 39 years old (age at diagnosis), 39 years old (age at baseline), 42 years old (current age)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Limitation of join mobility, joint stiffness (HP:0001376, HP:0001387)

CaseHPOFreeText: Patients in group 2 had normal mental development or only slightly delayed mental development and, therefore, could undergo active physical rehabilitation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Diagnosis of MPS I was confirmed by the biochemical determination of α-L-iduronidase activity deficiency in leukocytes and by molecular analysis.

CaseUrineGAGs: N/A

CaseERT: Yes, weekly infusions for 52-208 weeks (depending on the patient)

CaseBMT: N/A

Variant1: There are multiple variants listed for this patient (974-975ins12/L118, N181,IVS5(1486)C>T, IVS8(2537)insC,T410, V4541,R489, IVS10(3013)G>T, IVS12(3512)T>G) all of which have old, difficult nomenclature. Therefore, we cannot determine what the current nomenclature is.

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: See above.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 16 (group 2), Poland, male 32 years old (age at diagnosis), 32 years old (age at baseline), 35 years old (current age)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Limitation of join mobility, joint stiffness (HP:0001376, HP:0001387)

CaseHPOFreeText: Patients in group 2 had normal mental development or only slightly delayed mental development and, therefore, could undergo active physical rehabilitation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Diagnosis of MPS I was confirmed by the biochemical determination of α-L-iduronidase activity deficiency in leukocytes and by molecular analysis.

CaseUrineGAGs: N/A

CaseERT: Yes, weekly infusions for 52-208 weeks (depending on the patient)

CaseBMT: N/A

Variant1: There are multiple variants listed for this patient (974-975ins12/L118, N181,IVS5(1486)C>T, IVS8(2537)insC,T410, V4541,R489, IVS10(3013)G>T, IVS12(3512)T>G) all of which have old, difficult nomenclature. Therefore, we cannot determine what the current nomenclature is.

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: See above.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient D2, Druze religious group, located in lower Galilee.

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.928C>T (p.Q310X)

Variant1ClinVarID: 11915

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID:32829671

PMID:33208168

Gene:IDUA

Disease:NoDiseaseAssertion"

PMID: 25102484

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 10, Male, 2 months (onset), 2 months (diagnosed), 2 months (report), deceased (due to severe graft versus host disease)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0002240, HP:0001744, HP:0001537, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Hepatomegaly (moderate), Splenomegaly (moderate), Umbilical Hernia, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Delayed since early infancy)

CaseNotHPOs: HP:0000256 (Macrocephaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation at 5m

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.Q70X

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: p.Q33H/Q33H, p.L118/L118

ParentalGenotype: N/A

PreviouslyPublished N/A

Case: 2B-7

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.43; AcuStar CB/Ag = 0.17; ELISA CB/Ag = 0.20

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 9858249

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-2

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.45; AcuStar CB/Ag = 0.26; ELISA CB/Ag = 0.30

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

Variant: c.4541T>G (p.Phe1514Cys)

HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)

ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false

CAID:

gnomAD: absent

Case: P5, Chinese, female, 65yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 55.2, VWF:RCo (%) = 51.4, FVIII:C (%) = 1.3, VWF:CB (%) = 58.2, VWFpp (%) = 49.3, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 0.0, VWF: FVIIIB (%) = 0.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1911delC - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.2446C>T (p.Arg816Trp)

HGVS: NM_000552.4(VWF):c.2446C>T (p.Arg816Trp)

ClinVarID: 295; https://www.ncbi.nlm.nih.gov/clinvar/variation/295/

CAID: NA

gnomAD: MAF = 0.0002541 (9/35418 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6145654-G-A?dataset=gnomad_r2_1

Case: P37, Chinese, male, 20yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 0.6, VWF:RCo (%) = 0.5, FVIII:C (%) = 5.7, VWF:CB (%) = 0.6, VWFpp (%) = 0.7, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 9.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.1025_1032dup - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P39,Chinese, female, 21yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 13.0, VWF:RCo (%) = 14.3, FVIII:C (%) = 32.1, VWF:CB (%) = 12.9, VWFpp (%) = 12.1, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 2.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116-2delA

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P20, Chinese, female, 15yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 12; VWF:Ag (%) = 0.7, VWF:RCo (%) = 0.6, FVIII:C (%) = 3.9, VWF:CB (%) = 0.5, VWFpp (%) = 0.6, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2217_2220dup - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P54, Chinese, female, 30yo

DiseaseAssertion: VWD2A

FamilyInfo: both parents had mild type 1 VWD, a second undetected variant may exist in patient

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 27.0, VWF:RCo (%) = 1.8, FVIII:C (%) = 44.6, VWF:CB (%) = 1.1, VWFpp (%) = 11.2, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.0, VWFpp/VWF:Ag = 0.4, FVIII:C/VWF:Ag = 1.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.875–5T>G - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P73, Chinese, female, 16yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 29.6, VWF:RCo (%) = 35.4, FVIII:C (%) = 63.1, VWF:CB (%) = 35.0, VWFpp (%) = 78.3, VWF:RCo/VWF:Ag = 1.2, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.2279G>A (p.Arg760His)

HGVS: NM_000552.4(VWF):c.2279G>A (p.Arg760His)

ClinVarID: 31011; https://www.ncbi.nlm.nih.gov/clinvar/variation/31011/

CAID: NA

gnomAD: MAF = 0.00008009 (2/24972 alleles) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6155891-C-T?dataset=gnomad_r2_1

Case: P18, Chinese, male, 23yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 7; VWF:Ag (%) = 25.0, VWF:RCo (%) = 5.2, FVIII:C (%) = 39.0, VWF:CB (%) = 6.7, VWFpp (%) = 49.6, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4735G>A (p.Gly1579Arg)

HGVS: NM_000552.4(VWF):c.4735G>A (p.Gly1579Arg)

ClinVarID: 100385; https://www.ncbi.nlm.nih.gov/clinvar/variation/100385/

CAID: NA

gnomAD: absent

Case: Patient 8 (Family B), female, 49yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group A, Platelet count x103/μl = 178, PFA 100 sec = >300, SPA % = 9.5, MADR mg/mL = 0.75, VWF:Ag U/dL = 23.0, VWF:CB U/dL = 4.2, VWF:CB ratio = 0.19, VWF:RCo U/dL = 13.8, VWF:RCo ratio = 0.63, Platelet VWF U/dL = 74.0, FVIII U/dL = 50.0, BAT F/M = 12

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 3 (Family A), female, 38yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group A, Platelet count x103/μl = 207, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 67.9, VWF:CB U/dL = 3.6, VWF:CB ratio = 0.06, VWF:RCo U/dL = 33.1, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 128, FVIII U/dL = 54.5, BAT F/M = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 2 (Family A), female, 75yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group A, Platelet count x103/μl = 322, PFA 100 sec = NA, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 133, VWF:CB U/dL = 144.2, VWF:CB ratio = 1.1, VWF:RCo U/dL = 106, VWF:RCo ratio = 0.79, Platelet VWF U/dL = 129.5, FVIII U/dL = 126, BAT F/M = 3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4115T>G (p.Ile1372Ser)

HGVS: NM_000552.4(VWF):c.4115T>G (p.Ile1372Ser)

ClinVarID: 100327; https://www.ncbi.nlm.nih.gov/clinvar/variation/100327/

gnomAD: MAF = 0.00006175 (7/113356 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128469-A-C?dataset=gnomad_r2_1

Case: Patient 10 (Family C), female, 70yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 168, PFA 100 sec = >300, SPA % = 15, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 10.3, VWF:CB ratio = 0.23, VWF:RCo U/dL = 21.4, VWF:RCo ratio = 0.47, Platelet VWF U/dL = 202.0, FVIII U/dL = 53.2, BAT F/M = 15

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 20 (Family G), male, 58yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group B, Platelet count x103/μl = 213, PFA 100 sec = >300, SPA % = 12.6, MADR mg/mL = 0.3, VWF:Ag U/dL = 48.4, VWF:CB U/dL = 4.6, VWF:CB ratio = 0.10, VWF:RCo U/dL = 13.5, VWF:RCo ratio = 0.28, Platelet VWF U/dL = 175, FVIII U/dL = 56.4, BAT F/M = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 1 (Family A), female, 3yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group B, Platelet count x103/μl = 290, PFA 100 sec = >264, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 41.0, VWF:CB U/dL = 4.4, VWF:CB ratio = 0.11, VWF:RCo U/dL = 13.2, VWF:RCo ratio = 0.33, Platelet VWF U/dL = 76.4, FVIII U/dL = 36.1, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 14 (Family C), male, 39yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 210, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 61.3, VWF:CB U/dL = 10.4, VWF:CB ratio = 0.17, VWF:RCo U/dL = 18.5, VWF:RCo ratio = 0.3, Platelet VWF U/dL = 119, FVIII U/dL = 40.0, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 2 (Family A), male, 78yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 119, PFA 100 sec = >300, SPA % = 7, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.27, VWF:RCo U/dL = 28.4, VWF:RCo ratio = 0.63, Platelet VWF U/dL = 115, FVIII U/dL = 48.2, BAT F/M = 1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 18 (Family E), female, 1yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 28, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 142.9, VWF:CB U/dL = 97.0, VWF:CB ratio = 0.68, VWF:RCo U/dL = 102.7, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 135, FVIII U/dL = 98.1, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3946G>A (p.Val1316Met)

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID: NA

gnomAD: absent

Case: Patient 12 (Family C), female, 60yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 154, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 8.1, VWF:CB ratio = 0.18, VWF:RCo U/dL = 23.0, VWF:RCo ratio = 0.51, Platelet VWF U/dL = 127, FVIII U/dL = 68.0, BAT F/M = 18

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient A

DiseaseAssertion: VWD2N

FamilyInfo: Family 1

ParentalGenotype(s):

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871

CaseHPOFreeText: PTsec = 35.2, FVIII U/dL = 18.5, FVIII ratio = 0.29, VWF:Ag U/dL = 62.9, VWF:FVIIIB U/dL = 10.7, VWF:FVIIIB ratio = 0.17, VWF:CB U/dL = 53.3, VWF:RCo U/dL = 60.4, RIPA % = 74.7, PlatVWF:Ag U/dL = 90.4

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)

PreviouslyPublished: n/a

Gene: VWF

Variant: c.2561G>A (p.Arg854Gln); homozygous

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID: n/a

gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Case: Patient B

DiseaseAssertion: VWD2N

FamilyInfo: Family 2

ParentalGenotype(s):

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0011871

CaseHPOFreeText: PTsec = 37.2, FVIII U/dL = 36.7, FVIII ratio = 0.33, VWF:Ag U/dL = 109.8, VWF:FVIIIB U/dL = 25.7, VWF:FVIIIB ratio = 0.23, VWF:CB U/dL = 133.8, VWF:RCo U/dL = 94.5, RIPA % = 75.8, PlatVWF:Ag U/dL = 95.4

CaseNOTHPOs:

CaseNOTHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: "Genetic analysis was performed on exons 17-20 of the VWF gene as previously described" (PMID: 12393698)

PreviouslyPublished: n/a

Gene: VWF

Variant: c.2561G>A (p.Arg854Gln); homozygous

HGVS: NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/?new_evidence=false

CAID: n/a

gnomAD: MAF (European, Finnish) = 0.005692; https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Case: Patient 8, male, 9yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130

(Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: bleeding score = 3; VWF:Ag (%) = 57, VWF:RCo(%) = 43, VWF:RCo/VWF:Ag ratio = 0.75, VWF:CIIIB (%) = 35, VWF:CIIIB/VWF:Ag ratio = 0.61, VWF:CVIB (%) = 18, VWF:CVIB/VWF:Ag ratio = 0.32

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4196G>A

HGVS: NM_000552.5(VWF):c.4196G>A

ClinVarID: 293; https://www.ncbi.nlm.nih.gov/clinvar/variation/293/

CAID:

gnomAD: MAF = 0.01670 (173/10360 alleles) in the Ashkenazi Jewish population; https://gnomad.broadinstitute.org/variant/12-6128388-C-T?dataset=gnomad_r2_1

Case: P19, M/19

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 2, aPTT was 31 seconds, FVIII:C was 72%, VWF:RCo was 79 IU/dL, and VWF:Ag was 33 IU/dL, with a VWF:RCo/VWF:Ag ratio of 2.4. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 239 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case: P16, F/20

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 10, aPTT was 35 seconds, FVIII:C was 58%, VWF:RCo was 71 IU/dL, and VWF:Ag was 73 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 250 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case: P14, M/19

DiseaseAssertion: VWD1

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 1, aPTT was 46 seconds, FVIII:C was 38%, VWF:RCo was 49 IU/dL, and VWF:Ag was 24 IU/dL, with a VWF:RCo/VWF:Ag ratio of 2.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 240 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case: P13, M/15

DiseaseAssertion: VWD1

FamilyInfo: No family history

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 5, aPTT was 35 seconds, FVIII:C was 64%, VWF:RCo was 62 IU/dL, and VWF:Ag was 57 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.1. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 240 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: no mutation detected

HGVS:

ClinVar:

CAID:

gnomAD:

Case#: 03015, Age 37, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only member of family #0399.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 0, VWF:Ag: 17, VWF:RCo: 17.7, FVIII:C 15, VWF:CB 16

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: Not determined

ClinVar: N/A

CAID: N/A

gnomAD: N/A

Case#: 03044, Age 27, Female (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #03230

Parental Genotype: not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 22, VWF:RCo:18, FVIIIC:29, VWF:CB: 17

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: c.6699_6702dup (p.Cys2235ArgfsTer8)

ClinVar:

CAID:

gnomAD:

Case#: 21011, Age 54, Male, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2111.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NP_000543.2:p.Ser83Ter (c.246_247insT)

ClinVar: N/A

CAID: PA1139532036 CAID

gnomAD: N/A

Case#: 36004, Age 69, Female, Blood Type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3603.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 22, VWF:RCo:18.5, FVIII:C: 19, VWF:CB: 19

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2546+55G>T (p.=)

ClinVar: N/A

CAID: N/A

gnomAD: N/A

PMID: 28971901

Gene: von Willebrand Disease (VWF)

PMID: 35020809

Gene: VWF

III-1, Female 10 years old

disease assertion: VWD

**positive family history **

Parental Genotype: each has heterozygous, 3251G>A

CasePresentingHPOs: CaseHPOFreeText: BS 4, VWF Ag:0.38, *VWF:GPIbM:0.15,VWF:CB:0.13, VWFpp :0.76, FVIII:C:0.10

CaseNOTHPOs:* N.a.

CaseNOTHPOFreeText: n.a.

CasePreviousTesting: *GenotypingMethod: Sanger seqencing;

*PreviouslyPublished:n.a.

Gene:VWF Variant:c.3251G>A*

*HGVS:NM_000552.5:c.3251G>A

• *ClinVarID:Variation ID: 626952

*CAID:n.a.

*gnomAD:n.a.

Case: IP-5

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0000421

CaseHPOFreeRext: VWF:Ag <1%, VWF:RCo <6% and FVIII:C 2,4%. Epistaxis, oral cavity bleedings, gastrointestinal bleedings and hematomas.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: deletion of exons 4-34

HGVS:

ClinVarID:

CAID:

gnomAD:

Case:44‐year‐old male patient

DiseaseAssertion:type 3‐VWD patient

FamilyInfo:positive family hsiory: The proband and his sister both had low FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) levels, confirming the diagnosis of type 3 VWD. His father had nearly normal levels of FVIII:C (58 IU/dL) and VWF:Ag (57 IU/dL). His daughter had type 1 VWD with decreased FVIII:C (46 IU/dL) and VWF:Ag (19 IU/dL)., NGS identified a heterozygous VWF c.2328delT (p.A778Lfs*23) frame shift mutation only in the proband and his sister

ParentalGenotype(s):VWF missense mutation, c.6521G > T (p.C2174F), was found heterozygous in father, but mother not tested

CasePresentingHPOs:BAT score=16, Arterial thrombosis=ischemic stroke, FVIII:C*=1, VWF:Ag=3, Proein S:58, Protein C:100, antithrombin III=106, activated protein C resistance:2.9. CaseHPOFreeRext: Complete blood count showed normocytic anemia (hemoglobin 74 g/L), normal white cell (and differential), and platelet counts. He had prolonged activated partial thromboplastin time (APTT) (89.4 s (s) [reference range (RR), 28.0–44.0 s]) with greatly decreased FVIII:C (1 IU/dL) and VWF:Ag (3 IU/dL) (Table 1). Abdominal ultrasound scanning revealed fatty liver, normal gallbladder, spleen, pancreas, and kidneys. Four hundred ml of virus inactivated fresh frozen plasma (FFP) was transfused, and his VWF:Ag increased to 6 IU/dL. On Day 2 after admission, the patient abruptly experienced numbness and weakness in his right limb.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:n.a

GenotypingMethod:NGS

PreviouslyPublished: If applicable.

Gene: VWF

Variant:c.2328delT (p.A778Lfs*23) and c.6521G > T (p.C2174F)

HGVS:n.a.

ClinVarID:n.a.

CAID:n.a.

gnomAD: n.a.

PMID: 24924395

Gene: MYH7

"RSD had a significant antihypertensive effect and inhibited hypertensive-induced cardiac hypertrophy in SHRs and showed advantages compared with ACEI in decreasing BP in the early stage and in inhibiting myocardial fibrosis"

Case#: Subject number 18, female, 40 years (diagnosis), 65 years (baseline visit), 64 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 13, male, 43 years (diagnosis), 47 years (baseline visit), 45 years (ERT), 44 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 21, female, 20 years (diagnosis), 52 years (baseline visit), 45 years (ERT), 39 (age at ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 8, female, 49 years (diagnosis), 59 years (baseline visit), 52 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 1, female, 38 years (diagnosis), 50 years (baseline visit), 47 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: No mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 31, male, 49 years (diagnosis), 51 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 10, male, 13 years (diagnosis), 42 years (baseline visit), 39 years (ERT), 38 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 19, female, 24 years (diagnosis), 35 years (baseline visit), 29 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 6, male, 4 months (onset), 4 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: "no family history of neuromuscular disorders"

CasePresentingHPOs: HP:0004887 (respiratory failure requiring assisted ventilation), HP:0001639 (hypertrophic cardiomyopathy), HP:0001522 (death in infancy), HP:0002090 (pneumonia)

CaseHPOFreeText: infantile-onset, dysphagia at baseline

CaseNotHPOs:

CaseNotHPOFreeText: no tracheostomy, not on BiPAP

CasePreviousTesting: “GAA activity in peripheral blood leukocytes lower than normal”; on enzyme replacement therapy

Case1: Patient KW (this patient can be found in the GT database)

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225

(Epistaxis, gingival bleeding)

CaseHPOFreeText: Blood transfusions needed

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Surface expression of GPIIb/GPIIIa not reported for this patient

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: 4.5-KB DEL, EX2-9

LegacyVariant: N/A

ClinVar: 2890

CAiD: N/A

gnomAD: N/A

PreviouslyPublished: PMID: 1702098

Case5: (GT34), Gender, age and ethnicity not reported

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Inclusion criteria were patients with a history of mucocutaneous bleeding (Figure 1 shows a bar diagram of all the clinical manifestations in the patient cohort in this article)

CaseNotHPOs: N/A

ProteinExpression: Platelet receptor alphaIIbbeta3 protein was analyzed by flow cytometry followed by western blotting

Platelet Aggregation: Inclusion criteria for probands was absent or reduced platelet aggregation with agonists such as ADP, adrenaline, arachidonic acid, and collagen (no mention of ristocetin here-- this article does not tell us the specific aggregation for each proband in the paper)

CasePreviousTesting: For mutation analysis of ITGA2B and ITGB3 genes, DNA extraction from whole blood, PCR, heteroduplex PCR followed by CSGE and DNA sequencing were performed. All 30 exons of ITGA2B and 15 exons of ITGB3, as well as their promoters, were analyzed by CSGE following heteroduplex PCR.

Gene: ITGA2B

Variant: NC_000017.11:g.44393555C>T (g.951G>A promoter variant)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA913189168

gnomAD N/A

Case10: Female, 12 years old, Tamil Nadu India

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0006298

(Gingival bleeding, prolonged bleeding after dental extraction)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 1 for values

PlateletAggregation: See Table 1 for values

CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

Gene: ITGB3

Variant: 330_336TCCCCAGdel is not showing up in CAR noting it as Unregistered

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered

gnomAD: N/A

Case1: Male, 9 years old,

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: One brother, with no signs of bleeding diathesis

ParentalGenotype: Father is heterozygous for the c.2268C>T mutation and the mother is compound heterozygous with the c.2268C>T variant and c.2330C>T variant

CasePresentingHPOs: HP:0000421 Epistaxis

CaseHPOFreeText: Submucosal bleeding, hematomas, excessive achilles tendon bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: The patient's αIIbβ3 receptor count was estimated approximately 50% of that measured in a healthy age-matched control by quantitative flow cytometry

PlateletAggregation: Complete absense of platelet aggregation in response to ADP, arachidonic acid, epinephrine, collagen

CasePreviousTesting: Direct sequencing of the patients αIIb and β3 genes was perforemed

Gene: ITGB3

Variant: NM_000212.2:c.2248C>T (p.Arg750Ter)

LegacyVariant: (p.Arg724Ter)

ClinVar: 13564

CAiD: CA123246 (p.Arg750Ter)

gnomAD: N/A

Case19: (GT-21) Male, age or ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Proband GT-22 is related to GT-21 see Table 1

ParentalGenotype: Parents may be included in Table 1; however, not specified so no information

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)

PlateletAggregation: Minimal information (See Supplementary Table 3)

CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.

Gene: ITGB3

Variant: NM_000212.2:c.2302-1G>A

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400034626

gnomAD: N/A

Case1: Female, 35 day old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: The proband’s mother and father carry heterozygous c.512delC and c.1686delG mutations, respectively. Other parameters for parents are shown in Table 1.

CasePresentingHPOs: HP:0031364, HP:0000967

(Ecchymosis, petechiae)

CaseHPOFreeText: Large parietal and cervical cephalohaematoma, severe anemia

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry of platelet surface antigens revealed the absence of the αIIbβ3 complex.

PlateletAggregation: Prolonged closure time at PFA-100, absent ADP, adrenaline, collagen induced platelet aggregation, and ristocetin induced platelet aggregation at the lower limit of normal

CasePreviousTesting: Sequencing of ITGA2B and ITGB3 genes showed that proband is compound het.

Gene: ITGA2B

Variant: Can not conclusively determine if c.481delC and c.1654delG are the variants intended by the authors based on the available information.

LegacyVariant: N/A

ClinVar: N/A

CAiD: N/A

gnomAD: N/A

Case5: Patient ID E, Female, 1 year old, ethnicity not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978, HP:0000225

(Easy bruising, gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000967, HP:0000979, HP:0004406, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248

(Petechiae, purpura, recurrent epistaxis, GI bleeding, Intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)

CaseNotHPOsFreeText: Hemorrhage after dental, hemorrhage after trauma, ear bleeding, hematoma

ProteinExpression: N/A

PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin

CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.

Gene: ITGA2B

Variant: c.1460insAGGT (p.Ser477Gfs*111)

LegacyVariant: N/A

ClinVar: N/A

CAiD: Unregistered Variant

gnomAD: N/A

PMID: 12837870

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

PMID: 21930696

Gene: DLD

Disease: Pyruvate dehydrogenase E3 deficiency

MonDO: MONDO:0009529

InheritancePattern: Autosomal recessive

PMID: 17945527

Gene: ACADSB

Disease: 2-methylbutyrylglycinuria

MonDO: MONDO:0012392

InheritancePattern: AR

Gene: NAT8L

Disease: NAA deficiency

MonDO: MONDO:0013549

PMID: 19807691

PMID: 10915611

Gene: DBT

Disease: Maple syrup urine disease

MonDO: MONDO:0009563

InheritancePattern: AR

PMID: 32360764

Variant NM_000280.5:c.333C>A(p.Val111=)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Notes Proband with confirmed aniridia and confirmed de novo appearance of the variant, summary in table 1, proband information in the "splice variant" section. It is noted however that the authors do not include the parental genotype or phenotype data.

Clinical Lab The Wessex Regional Genetics Laboratory has been contacted for variants c.333C>A and c.1183G>C, there is no additional information than what is in the table and if familial or de novo is claimed it is because parental samples were collected and tested negative for the variant in the published proband

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The proband reported has clinical features of neurofibromatosis, with a de novo donor splice site variant in NF1, as well as a 12-bp deletion in RAB39B, which the authors assert was responsible for the phenotypes of severe ID, behavioral problems and aggressiveness.

CaseID D

VariantInPub IVS2+9G>A

MANE NM_001368894.2:c.-129+9G>A

Zygosity heterozygous

PhenotypesProband HP:0000568, HP:0000482, HP:0000518, HP:0000639, HP:0000647, HP:0000491

FamilyInfo No family or segregation information was included

SpliceFormVariant No RT-PCR or northern blot to confirm the intronic substitution lead to a splice variant

PMID 22830481

Disease Pulmonary fibrosis/ bone marrow failure syndrome

GroupPresentingHPOs: only shared phenotype was reduced GALNS activity in leukocytes

GroupGenotypingMethod: Sanger seq of amplified exons

NumberMales: 15

NumberFemales: 6