Case#: Green_Malmo_6 (assumed male)

DiseaseAssertion: Severe Hemophillia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C <1%, FIX:Ag: 26-34)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T (p.Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case #: young male, China

DiseaseAssertion: Hemophilia A, moderate (FVIII:C 2.6%)

FamilyInfo: Grandfather had Hemophilia A, making his mother an obligate carrier

ParentalTesting: Mother was tested and confirmed to be a carrier using Sanger and cDNA sequencing

CasePresentingHPO: HP:0011890 (prolonged bleeding following procedure), HP:0040232 (delayed onset bleeding), HP:0001058 (poor wound healing)

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Entire VIII coding region and exon-intron boundaries were sequenced and amplified. A pSPL3 in-vivo assay showed a two-nucleotide inclusion at the 3' splice site of intron 22, which was confirmed using Sanger sequencing.

Gene: F8

Variant: NM_000132.3:c.6430-3C>G

ClinVar: No

CAID: CA873369662

gnomAD:

Case#: 52HBT167 (Turkish; assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Reduced factor IX activity (FIX:C:3.9)

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)

LegacyVariant: c.112G>A (p.Cys-19Tyr)

ClinVar: Absent/Not Reported

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: HB_132 (assumed male)

DiseaseAssertion: Mild-Moderate Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: N/A

CasePresentingHPOsFreeText: Mild-Moderate Hemophilia B, Quality parameters given as read depth and strand bias for the mutated positions: 3098/0.51

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.82T>C (p.Cys28Arg)

ClinVar: 10657

CAID: CA255450

gnomAD: Absent/Not Reported

Case#: Guo_Proband_2 (assumed male; Chinese)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity FIX:C:2.1%; FIX:Ag:1.6

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.59T>C (p.Leu20Ser)

ClinVar: Absent

CAID: CA414434363

gnomAD: Absent/Not Reported

Case#: Guo_Proband_3 (assumed male; Chinese)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs:

CaseHPOsFreeText: reduced factor IX activity FIX:C: 2.9%; FIX:Ag: 3.0)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)

ClinVar: Absent

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: Patient Q (male, 83 y/o, born in South Germany)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Brother died from a life threatening bleeding complication under phenprocoumon therapy

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858, HP:0012233

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2%), muscle hematoma of the extremities, subcutaneous bleed of the body and lower extremities.

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.110C>T (p.Ala37Val)

ClinVar: Absent

CAID: CA414435437

gnomAD: Allele Frequency (European-non Finnish): 0.00002186

Case#: Pezeshkpoor_Patient_O (male, 36 y/o, from Switzerland)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0002625, HP:0011858

CaseHPOsFreeText: deep vein thrombosis, low FIX:C levels (<1%), prolonged aPTT of 90 seconds, diffuse muscle bleeding

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

AdditionalCaseInfo: Sequencing of SERPINC1 revealed a splice site mutation located at c.1154-14G>A

Case#: Pezeshkpoor_Patient_M (male, 58 y/o, from Switzerland)

DiseaseAssertion: Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: spontaneous bleeding symptoms from the blood, the mouth, the tongue, and epiglottis, low FIX:C levels

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: 18

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1068G>T

LegacyVariant:

ClinVar: No

CAID: CA414445683

gnomAD:

Case#: 33

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.103G>T

LegacyVariant:

ClinVar: No

CAID: CA414435383

gnomAD:

Case#: 25

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1204G>A

LegacyVariant:

ClinVar: No

CAID: CA414446446

gnomAD:

Case#: 12

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.761G>A

LegacyVariant:

ClinVar: No

CAID: CA414443235

gnomAD:

Case#: 5

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.305G>T

LegacyVariant:

ClinVar: No

CAID: CA414437422

gnomAD:

Case#: 41

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1135C>T

LegacyVariant:

ClinVar: No

CAID: CA255391

gnomAD:

Case#: 17

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 3%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1025C>T

LegacyVariant:

ClinVar: No

CAID: CA255381

gnomAD:

Case#: Meireles_Proband_2 (assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Trp)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Meireles_Proband_4 (assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Family HB55

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>T (p.Arg43Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: Gostout_Proband_189 (assumed male, Asian (from India))

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 3%)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T (p.Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Gostout_Proband_280 (assumed male, Asian (from Japan))

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 1.8%)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: 8

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.349T>C

LegacyVariant:

ClinVar: No

CAID: CA414437669

gnomAD:

Case#: 16

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 1.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.427C>G

LegacyVariant:

ClinVar: No

CAID: CA414438921

gnomAD:

Case#: 11

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.676C>T

LegacyVariant:

ClinVar: No

CAID: CA255350

gnomAD:

Case#: HB15 (assumed male, Tunisian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX: <1)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Patient B (assumed male)

DiseaseAssertion: Moderate, Sporadic Hemophilia B

FamilyInfo: Patient B is deceased and only a DNA sample was available; his two sisters and mother are carriers

ParentalTesting: Mother was heterozygous for the variant

CasePresentingHPOs: None

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

LegacyVariant: c.6365 G>A (p.Arg-4Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Ivaskevicius_Proband_LT65 (assumed male, Lithuanian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 0)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T (p.Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: N/A

CaseHPOsFreeText: N/A

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.71T>C (p.Leu24Pro)

ClinVar: Absent

CAID: CA414434410

gnomAD: Absent/NotReported

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: N/A

CaseHPOsFreeText: N/A

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.59T>C (p.Leu20Ser)

ClinVar: Absent

CAID: CA414434363

gnomAD: Absent/NotReported

Case#: Li_Proband_1 (male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: N/A

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.82T>C (p.Cys28Arg)

ClinVar: 10657

CAID: CA255450

gnomAD: Absent/Not Reported

Case#: Patient A (assumed male)

DiseaseAssertion: Severe (sporadic) Hemophilia B

FamilyInfo: Variant also localized in affected brother, mother (Native American descent) is deceased but maternal grandmother and two maternal aunts screened negative, researchers believe this de novo mutation originated during either grandparent’s gametogenesis.

ParentalTesting: Mother deceased, no mention of father

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX Clotting Activity (U/dl): < 1, Antigen Level (U/dl): < 1

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.50T>A (p.Ile17Asn)

LegacyVariant: c.79T>A (p.Ile-30Asn)

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case1: 21 year old, male patient, bearing a F8 frameshift mutation with severe Hemophilia A.

DiseaseAssertion: Severe Hemophilia A

Variant: NM_000132.3:c.3167del

ClinVar: Not noted in ClinVar

CAID: CA915940211 (Previously not registered)

DiseaseEntity: Factor VIII deficiency

Inheritance Pattern: No inheritance assertion

Case#: Liu_Proband_56/439/440/486/830 (assumed male; Chinese)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: Absent

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Liu_Proband_438 (assumed male; Chinese)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: Absent

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Salviato_Proband_2164 (male, Chinese)

DiseaseAssertion: Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)

ClinVar: Absent

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: Salle_Proband_J-C L (male, 23 y/o, white)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: family history is negative for any haemostatic disorder

ParentalTesting: family history is negative for any haemostatic disorder

CasePresentingHPOs: HP:0011858, HP:0012233, HP:0000421

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <0.01 % FIX:Ag: 0.46), muscular haematoma, haemarthrosis, nose bleeding

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Nummi_Proband_6 (assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0001929 (FIX baseline clotting activity: 1

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)

ClinVar: Absent

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: Oldenburg Cases A, B and C (A: 66 y/o, B: 38 y/o, C: 30 y/o (all in Germany))

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: No bleeding tendency noted in any of these patients family history

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: severe bleeding at each occasion of oral anticoagulation with phenoprocoumon, bleeding was located in the muscles of the upper leg (patients A and C) and scrotum, left calf and thigh musles (patient B), reduced factor IX levels

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

LegacyVariant: p.Ala-10Thr

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

AdditionalCaseInfo: all patients were unrelated up to the third generation. However, the parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)

CaseInfo: P2 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0004846, HP:0001892

CaseHPOFreeText: Low FVIII levels (undetectable FVIII:C levels and significant decrease in FVIII:Ag levels: 1.7% ± 1.1), prolonged bleeding after surgery, mild bleeding tendency

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection were also performed.

Gene: F8

Variant: NM_000132.3:c.943del

CAID: CAID:CA255085

gnomAD: Absent/Not Reported

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0001929

CasePresentingHPOsFreeText: reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.84T>G (p.Cys28Trp)

ClinVar: Absent

CAID: CA414434487

gnomAD: Absent/Not Reported

Case#: Weinmann_Family 9248

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: 16 of the families were from the Pacific Northwest, 4 from Colorado, and 6 were referred from elsewhere in the United States

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 37)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Belvini_Proband_15 (male, Italian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Riegelsberg (male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Mother carries only the G-to-A transition (age at conception: 30 y/o). Origin of variant cannot be proved, since maternal grandparents were deceased at time of report.

ParentalTesting: Mother carries only the G-to-A transition, father shows to not be affected (figure 1)

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX Coagulant %: < 1, FIX Antigen %: < 1

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.8G>A (p.Arg3His)

LegacyVariant: c.37G>A

ClinVar: 695909

CAID: CA10529706

gnomAD: Filtering AF: 0.0002304 (no homozygotes)

Case: IV-1

CasePresentingHPOsFreeText: Both affected subjects had symptoms of nonprogressive nyctalopia since childhood, while the proband also had photophobia. Both cases had a distance visual acuity of 20/50 or better in each eye, normal contrast sensitivity, and an incomplete type of Schubert-Bornschein ERGs. The proband also had high myopia, a mild red-green color deficit, hypopigmented fundus, and foveal hypoplasia with no evidence of chiasmal misrouting.

CasePreviousTesting:

CaseGenotypingMethod: Haplotype analysis was performed on all three members of the family using polymorphic microsatellite DNA markers flanking CACNA1F (DXS1003 and DXS7132. All exons and exon/intron boundaries of CACNA1F and nyctalopin (NYX) genes were sequenced in the proband (case IV 1)

Variant: c.1807G>C mutation (p.G603R)

ClinVarID: or CAID: CA412914688

gnomAD: not found in gnomAD v2.1.1

AddCaseInfo: The mutation is located on the S3 helical trans-membrane domain repeat II of the CACNA1F gene (CACNA1F encodes for the α1 subunit of a L-type Ca2+ channel that contains four repeat domains, each of which has six transmembrane domains (S1–S6); NP_005174.2). The p.G603R was predicted to be possibly damaging by Polyphen v. 2.09 with a PSIC score difference of 1.525. The mutation was predicted also to affect protein function by SIFT with a score of 0.00.

PreviouslyPublished:

Case#: Family 1002, Greek, 26 years, now living in USA.

CaseHPOs:

CaseHPOsFreeText: Difficulty adapting to the dark from early childhood. Fundus exam (see Fig 2A) at age 26 years showed yellow-white dots, sharply demarcated, sparing the macula and radiating from the perimacular region; well-defined foveal reflex, absent pigmentary changes, normal vascular caliber.

CaseNotHPOsFreeText: No other associated ocular or systemic disorders.

CasePreviousTesting: RBP3 excluded by heteroduplex analysis and sequencing (this study). Affected siblings had non-concordant pattern for an intragenic RFLP analyzed by Southern blot.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing

Variant: c.712G>T (p.Gly238Trp) (homozygous)

ClinVar: 8003

CAID: CA119196

gnomAD: The highest population MAF in gnomAD v2.1.1 is 0.0004532 (Latino/Admixed American); no homozygotes in any population.

CaseAddInfo: Parents are seventh cousins

Not scoring because another patients with this genotype has already been included.

Case: Case_47

CasePresentingHPOsFreeText: RP, A cohort of 168 unrelated Korean patients with IRD was recruited from the Department of Ophthalmology, Seoul National University Hospital (SNUH), from October 2008 to January 2019. A detailed family history was obtained from each patient to construct a pedigree. All patients underwent a detailed ophthalmic history and ophthalmic examinations, including best-corrected visual acuity, slit-lamp biomicroscopy, fundus photography, optical coherence tomography, fluorescein angiography, visual field tests, and full-field electroretinograms. Clinical diagnosis was determined by at least two retinal specialists (DJM and UCP).

CasePreviousTesting: WES

CaseGenotypingMethod: WES was performed at the Genomics core facility of the Center for BioMarkers (SNUH, South Korea) using an Illumina NextSeq500

Variant: c.2514_2515del, p.N838fs

ClinVarID: or CAID: CA2573335125

gnomAD:

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#:P3-ES; II.3, F, Age of report: 58 y.o., Ethnicity: Spanish.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0005101 (High-frequency hearing impairment/non-progressive hearing loss at high frequencies), HP:0000543 (Optic disc pallor/pale optic disc), HP:0500081 (Pseudophakia), HP:0012832 (Bilateral),

CaseHPOFreeText: F3 is a consanguineous family (parents are second cousins) of Spanish origin with three affected and two unaffected siblings (Fig. 1c).

The index case (P3-ES; II.3) is a 58 years-old female with a typical RP and a late-onset, moderate, non-progressive hearing loss at high frequencies (Fig. 3). She had a BCVA of 0.3 D with a 10° central visual field in either eye, and presented a typical RP fundus with a pale optic disc, vessel attenuation, and pigment deposits in the periphery (with alterations of the RPE at the macular area). She had bilateral pseudophakia and did not present CME (Table 2).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Custom panel of 117 genes associated with IRDs and WES.

Variant: Variant 1: NM_021831.6:c.1565del (p.Gly522AspfsTer4). Variant 2: NM_021831.6:c.908G>A (p.Arg303His).

ClinVar: Variant 1: N/A. Variant 2: 1044022.

CAID: Variant 1: CA3051368245. Variant 2: CA1567753.

gnomAD: Variant 1: N/A. Variant 2: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband's affected brothers were not collaborative for clinical examination in this study, but the proband referred that her elder brother (II.1) uses hearing aids and her younger brother (II.5) has a mild hearing impairment, both presenting also RP. Her unaffected siblings (II.2, II.4) do not present RP or hearing impairment. The three affected members were initially referred for genetic testing in 2015 with a clinical diagnosis of isolated RP. One of them (II.3, P3-ES) was analysed using a custom panel of 117 genes associated with IRDs, but no pathogenic variants were identified [27]. Subsequently, WES performed in two affected siblings (II.3, II.5) revealed compound heterozygous pathogenic variants in AGBL5 (Table 1) which segregated with the disease in the family (Fig. 1c).

CasePMIDs: N/A.

FamilyName: Selmer_Family

FamilyPresentingHPOFreeText: autosomal dominant pericentral retinal dystrophy (adPRD). Sixteen individuals (aged 23–78 years) were ophthalmologically examined as part of this project and 10 of them were assigned a diagnosis of PRD (Table 1). The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis

CountryOrigin: Norway

FamilyPreviousTesting: We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease.

FamilyMethod1:

FamilyMethod2:

FamilyGenotypingMethod: Mutations in the RHO, RP1, RDS and IMPDH1 genes as a cause of adRP in this family were excluded in a separate study published elsewhere (Grøndahl et al. 2007). Genotyping was performed using the Affymetrix GeneChip® Human Mapping 10 K 2.0 array (Matsuzaki et al. 2004), according to the supplier’s protocol. All three exons of the TOPORS gene, including exon–intron boundaries, were sequenced.

Affected:

Unaffected:

Segregations:

PublishedLOD: 7.3

AddSegregationInfo: Preliminary results of linkage analysis showed a linkage peak with a LOD (logarithm of the odds) score of 2.6 covering the recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a missense mutation c.1205a>c was identified in exon 3 in all affected members, leading to a p.Q402P amino acid substitution. The mutation showed complete co-segregation with the disease (Fig. 1) in all members tested, and linkage analysis yielded a LOD score of 7.3, assuming complete penetrance and a mutation frequency of 0.001.

ProbandLabel: Selmer_Proband

Variant:

gnomAD: absent in gnomAD

CAID: CA373170940

Case: Patient 1

CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.

CasePreviousTesting:

CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.

Variant: c.1075G>A (p.Gly359Arg)

ClinVarID: or CAID: CA412919833

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Patient 5

CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.

CasePreviousTesting:

CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.

Variant: 1684+1G>A

ClinVarID: or CAID: CA412915988

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#: F2-II:1, F, Age: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0001328 (Specific learning disability/earning difficulties)

CaseHPOFreeText: FAF imaging in three patients demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

OCT imaging also demonstrated loss of outer retina with partial preservation of the inner segment ellipsoid band in patient F2-II:1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). All patients developed posterior subcapsular cataract. Patient F2-II:1 had learning difficulties but no other symptoms suggestive of syndromic disease. There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). Fundus autofluorescence imaging demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

On OCT, there was outer retinal atrophy with variable preservation of photoreceptors most apparent in F2-II:1 with a centrally preserved inner segment ellipsoid band (Fig. 2D). Optical coherence tomography imaging demonstrated intraretinal cysts of the inner nuclear layer, which responded to topical carbonic anhydrase inhibitors (Figs. 2E, 2H, 2K). Electrophysiology demonstrated rod and cone system dysfunction (Table 1).

Two affected siblings from family 2 (GC15894) were homozygous for the missense variant c.323C>G:p.(Pro108Arg).

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Affected sister F2-II:3 was noted to have the following:

Focal parafoveal increased autofluorescence in F2-II:3 (G), likely representing cystoid macular edema.

Very limited photoreceptor preservation for F2-II.3

Focally increased autofluorescence corresponding to macular edema in F2-II:3

CasePMIDs: N/A.

Case#: II.1, F, Age of Onset: 7-8 y.o., Ethnicity: Turkish.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa)

CaseHPOFreeText: Proband comes from a consanguineous family.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Exome sequencing.

Variant: NM_021831.6:c.883G>A (p.Asp295Asn).

ClinVar: 242932.

CAID: CA10584033.

gnomAD: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband has two affected siblings. They were evaluated by Sanger sequencing. II.3 had age of onset at 7-8 y.o and was noted to have mixed astigmatism and mental retardation

II.4 had age of onset at 12 y.o and was noted to have

Both siblings were homozygous for the same variant as the proband.

Since targeted analysis of all genes linked to retinal disorders did not reveal a pathogenic mutation in pedigree E, we extended our search to include the entire exomes of the two affected family members. With this approach, a homozygous missense mutation (Asp295Asn) was detected in the deglutamylase gene AGBL5 which was confirmed in all affected family members while the unaffected parents are heterozygous carriers.

CasePMIDs: N/A.

Case#: 17-year-old boy, M, Age of Report: 17 y.o., Ethnicity: Indian/Pakistani descent.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0100832 (Vitreous floaters), HP:0030786 (Photopsia/ intermittent photopsia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001489 (Posterior vitreous detachment), HP:0030644 (Blind-spot enlargement),

CaseHPOFreeText: Proband came from a consanguineous family-multi-generational pedigree indicated his parents were first cousins of Indian/Pakistani descent.

A 17-year-old boy was referred for a history of pre- sumed pseudotumor cerebri associated with constricted visual fields. Prior to presenting at our clinic, he was observed to have retinal pigment and bilateral optic nerve edema. CT, MRI, and MRV were all normal. Lumbar puncture showed monocytes and lymphocytes but was otherwise normal. Given the lack of radiologic abnormalities and some recent weight gain, the diagnosis of pseudotumor cerebri was made and he was pre-scribed acetazolamide.

During the visit at our clinic, the patient reported a history of nyctalopia and some floaters in the right eye. He recalled, after starting the acetazolamide, some intermittent photopsia and visual obscurations. He was otherwise well and had lost 12 pounds over the last 2 months at the request of his doctor.

On our examination, best corrected visual acuity was 20/20–2 in each eye (−3.75 + 2.25 × 80 OD, −4.00 + 2.25 × 95 OS). Pupillary responses and eye movements were normal. Ishihara color plate testing was normal. Slit lamp examination and Goldmann applanation tonometry were normal. Fundus examination showed “bone spicule” pigmentary clumping scattered for 360 degrees in the mid periphery of each eye, internal limiting membrane irregularities over the macula, and a posterior vitreous detachment in the right eye (Figure 1a). The optic nerves were raised and irregular, consistent with optic nerve drusen (Figure 1b). There was no active edema or subretinal fluid.

OCT showed a distinct loss of photoreceptors outside the central macula. The subfoveal ellipsoid zone was also patchy in each eye (Figure 1c). Fundus autofluoresence (FAF) showed a hyperfluorescent ring within the macula and blocking of pigment beyond the macula (Figure 2a). Goldmann visual field testing showed an enlarged blind spot in each eye and generalized constriction of the isopters, in particular the I4e (Figure 2b). Multifocal electroretinogram (ERG) was severely abnormal with some central sparing. Full field ERG was isoelectric. B-scan ultra-sonography showed optic nerve drusen bilaterally (Figure 2c).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Retinitis Pigmentosa Panel and My Retina Tracker Program Panel Plus.

Variant: NM_021831.6:c.1295A>T (p.Asp432Val).

ClinVar: N/A.

CAID: CA346180826.

gnomAD: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27056068-A-T?dataset=gnomad_r4.

VariantEvidence:N/A.

CaseAddInfo: Segregation analysis revealed that the unaffected mother and father were heterozygous for AGBL5: c.658C>T c.1295A>T, p. (Asp432Val).

CasePMIDs: N/A.

Case#: Patient 5, male, 16 years (at report)

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: Poor vision and photophobia since the age of 4. BCVA was 0.4 LogMAR in right eye and 0.52 LogMAR in left eye with a refractive error of −5.75 sph −3.00 cyl/15° D in right eye and of −6.00 sph −3.50 cyl/170° D in left eye. Fundus exam showed normal optic disk, a loss of the foveal reflex, and peripheral RPE mottling. Fundus autofluorescence revealed a central hypofluorescence with a mild perifoveal hyperfluorescent area in both eyes while OCT imaging showed a foveal photoreceptor disruption associated with a normal central macular thickness and relative sparing of paracentral retina (Figure 6). Flash full-field ERG recordings showed reduced responses mostly for the photopic component. Visual fields display a central scotoma.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: Variant 1) c.409C>T (p.Arg137Ter)(paternal) Variant 2) c.77C>A (p.Thr26Asn)(maternal)

ClinVar: Variant 1) 60755; Variant 2) N/A

CAID: Variant 1) CA144657; Variant 2) CA356375011

gnomAD: Variant 1) 0.00001764 (European non-Finnish). No homozygotes in any population. Variant 2) Not in gnomAD

VariantEvidence: Variant 1) no nonsense-mediated decay of mRNA was previously reported (Roosing et al, 2013). In the current paper, structural analysis showed that truncation would delete the α4, β6, and α5 structural elements. The lack of β6 and α5 would most likely prevent the correct α/β fold from forming, affecting the guanine nucleotide binding pocket, and resulting in protein degradation. Variant 2) Molecular dynamics simulations of p.Thr26Asn in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP. The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state.

CaseAddInfo: Parents and brother are clinically unaffected. The father and brother are heterozygous for the nonsense variant and the mother is heterozygous for the missense variant.

Case#: Patient 303-002, female, N. European; 16 years old at report in PMID: 1428198 (Case 3)

CaseHPOs: CaseHPOsFreeText: “Peculiar peripheral fundus pigmentation” was noted on eye exam at age 12 years, “slight difficulty in the dark” (PMID 1428198, Case 3). Fundus and ERG abnormalities reported to be characteristic of Oguchi disease. ERG abnormalities included, after 45 min of dark adaptation, a nondetectable rod response to single flashes of dim blue light and a normal cone response to 30-Hz white flickering light.

CaseNotHPOsFreeText: Visual acuity was 20/20 bilaterally at age 16 years. Eye exam was normal except for fundus changes. Normal physical examination, laboratory tests (no details given on which tests were performed), and x-rays (no details given on which bones were X-rayed)(PMID: 1428198)

CasePreviousTesting: No variants identified in SAG (by SSCP analysis). The authors note specifically that SAG Asn309(1-bp del) was absent (a positive control with this variant was included in the study).

CaseMethod1: SSCP

CaseMethod2: Sequencing

CaseGenotypingMethod: Single-strand conformation polymorphism (SSCP) analysis of the coding exons and exon/intron boundaries of GRK1 and SAG.

Variant: 1) NM_002929.3(GRK1):c.1139T>A (p.Val380Asp) (paternal) 2) NM_002929.2:c.1607_1610del (p.Asp537ValfsTer7) (maternal)

ClinVar: 1) 13010; 2) N/A

CAID: 1) CA034664; 2) CA7066374

gnomAD: 1) 0.00006786 (European non-Finnish, 5 alleles total, no homozygotes) 2) 0.001541 (South Asian; 89 alleles total in all populations; no homozygotes)

VariantEvidence: p.Val380Asp introduces a negatively charged residue into the catalytic domain and would therefore likely interfere with kinase activity. However, no functional studies are available.

CaseAddInfo: Family #F277 (Figure 2)- The father is heterozygous for c.1139T>A (p.Val380Asp), and the mother is heterozygous for c.1607_1610del. Her affected sister (Case 4 in PMID: 14281981) has the same genotype as 303-002. Two unaffected brothers are heterozygous for p.Val380Asp. Both sets of grandparents are from the same small town in Hungary (PMID: 14281981).

CasePMIDs: 14281981

Score: 1. This individual and her sister have classic features of Oguchi disease and both are compound heterozygous for a missense variant (p.Val380Asp) and a frameshift variant in GRK1. SAG analysis, by SSCP, was normal. The highest population minor allele frequencies of these variants in gnomad v2.1.1 are 0.00006786 (European non-Finnish, 5 alleles total, no homozygotes) and 0.001541 (South Asian; 89 alleles total in all populations; no homozygotes) respectively. The score is reduced because SAG was analyzed by SSCP and hence it is possible that causative variants in that gene may have been missed, and because there is no functional evidence to support the deleterious impact of the missense change.

Case: Shamieh_ItalianPatient

CasePresentingHPOsFreeText: RCD

CasePreviousTesting:

CaseGenotypingMethod: The next generation sequencing (NGS) panel was selected from the SureSelect Human All ExonKits Version 4 (Agilent, Massy, France) and covers 198 IRD genes in total. Identified variants in KIZ (NM_018474.4) were validated by direct Sanger sequencing, and co-segregation analyses was performed in the DNA of available family members as previously described [ 9 ]. Similarly, the presence of the two mutations c.52G>T, p.Glu18 and c.119_122del, p.Lys40Ilefs14 in the fibroblast cell line of patient CIC01225 was confirmed by direct Sanger sequencing using genomic primers and conditions as previously described [9]

Variant: c.3G>A (p.M1?) homozygous

ClinVarID: or CAID: CA408488039

gnomAD: 0.00004892 allele frequency in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#: P8, Female, 2.7 years (diagnosed), 4.5 (report), 15 kg (weight), 90 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous; P7 is a sibling of P8

CasePresentingHPOs: HP:0001999, HP:0001433, HP:0001387, HP:0007957 (Facial Dysmorphic Features, Hepatosplenomegaly, Hernia(Ombelical), Corneal Opacity)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency)

CaseNotHPOs: HP:0001249, HP:0000943, HP:0001387, HP:0000238 (Mental Retardation, Multiple Dysostosis, Joint Stiffness, Hydrocephalus)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA Enzyme activity 10 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 44 (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

Case#: P6, Female, 11.4 years (diagnosed), 12.6 (report), 24 kg (weight), 121 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous; P5 is a sibling of P6

CasePresentingHPOs: HP:0001999, HP:0000943, HP:0001387, HP:0001433, HP:0001387, HP:0007957 (Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatosplenomegaly, Hernia(Ombelical), Corneal Opacity)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Stenosis & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, (Mental Retardation)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA Enzyme activity 10 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 22 (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

Case#: P7, Male, 0.9 years (diagnosed), 1.7 (report), 11 kg (weight), 78 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous: P8 is a sibling of P7

CasePresentingHPOs: HP:0001999, HP:0002240, HP:0001387, HP:0007957 (Facial Dysmorphic Features, Hepatomegaly, Hernia(Ombelical), Corneal Opacity)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, HP:0000943, HP:0001387, HP:0000238 (Mental Retardation, Multiple Dysostosis, Joint Stiffness, Hydrocephalus)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA Enzyme activity 9 (% to the reference range mean)

CaseUrineGAGs: N/A

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

Case#: Taiwanese newborn

DiseaseAssertion: MPS-I

FamilyInfo: Probands mother and father had genetic testing conducted.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Patient had lower enzyme activities than the reference value, 9.03–69.52 µmol/L blood*20 h. Not specifically stated which value is the patient's but IDUA activity for 2 newborns were between 6.8–37.0 µmol/g protein/h.

CaseUrineGAGs: uGAG quantification results were in the normal range for all three patients (reference range; 44.6 ± 23.7 mg/mmol creatinine); however, the 2-D EP results showed unclear HS but significant DS level for two affected patients.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.344G > T (D119Y). The article states that the point mutation was c.344G>T (D119Y) but it is assumed that this is a typo.

Variant1ClinVarID: 2432701

Variant1CAID: CA2801882

Variant2: c.99T>G (H33Q)

Variant2ClinVarID: 92651

Variant2CAID: CA145894

AdditionalVariants: N/A

ParentalGenotype: c.344G > T (D119Y) was inherited from the father and c.99T > G (H33Q) was inherited from the mother.

PreviouslyPublished Yes, PMID:24053568

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: 0.2 ± 0.1 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1205G>A (p.W402X)

ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 1.8% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 4.9 ± 1.5 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.826G>A (p.E276K)

Variant1ClinVarID: 3233261

Variant1CAID: CA355962355

Variant2: c.826G>A (p.E276K)

ClinVarID: 3233261

Variant2CAID: CA355962355

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.3% residual activity at 37 °C

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.8 ± 0.3 nmol/mg/h IDUA activity at 37 °C

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)

ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.6% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 1.6 ± 0.1 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.979G>C (p.A327P)

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: N/A

ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 1.2% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.3 ± 1.1 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.826G>A (p.E276K)

Variant1ClinVarID: 3233261

Variant1CAID: CA355962355

Variant2: c.826G>A (p.E276K)

ClinVarID: 3233261

Variant2CAID: CA355962355

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.9% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.5 ± 0.2 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1861C>T (p.R621X)

Variant1ClinVarID: 11917

Variant1CAID: CA256118

Variant2: c.974ins12 in paper but nomenclature is c.878_889dup (p.Thr293_Tyr296dup)

ClinVarID: 550382

Variant2CAID: CA2802114

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, Han origin, male, 2 years old (age at diagnosis).

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.6 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.713T>G (p.L238R)

Variant1ClinVarID: 2581619

Variant1CAID: CA2802064

Variant2: c.882dupC (Paper refers to the variant as c.883dupC, there is a typo in the article where all duplication variants are one base pair off)

Variant2ClinVarID: 1076379

Variant2CAID: CA2499217013

AdditionalVariants: N/A

ParentalGenotype: Father - c.882dupC (In article - c.883dupC). Mother - c.713T>G. 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

Case#: Patient 53, female, Han origin, 4 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

Variant2: c.1402+1G>T

Variant2ClinVarID: 1323099

Variant2CAID: CA355964387

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

Case#: Patient 48, male, Han origin, 19 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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.536C>G (p.T179R)

Variant1ClinVarID: 556358

Variant1CAID: CA355961718

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 51, female, Han origin, 1 year 6 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.4 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.46_57del12 (p.Ser16_Ala19del)

Variant1ClinVarID: 92643

Variant1CAID: CA220509

Variant2: c.792+1G>C

Variant2ClinVarID: N/A

Variant2CAID: CA355962280

AdditionalVariants: N/A

ParentalGenotype: Father - c.46-57del12, Mother - c.792+1G>C. 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

Case#: Patient 8, male, Han origin, 6 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 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.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

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

Case#: Patient 46, male, Han origin, 9 years 6 months old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hernia (HP:0001387, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hepatosplenomegaly, Airway obstruction (HP:0001263, HP:0000256, HP:0011369, HP:0001433, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.2 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.532G>A (p.E178K)

Variant1ClinVarID: 2203495

Variant1CAID: 355961709

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 15, male, Han origin, 6 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay (HP:0001263)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.4 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.349delT (p.Tyr117ThrfsTer16)

Variant1ClinVarID: 1451219

Variant1CAID: CA2573137553

Variant2: c.1898C>T (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

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

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: R363C

Variant1ClinVarID: 557205

Variant1CAID: CA2802184

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: L490P

Variant1ClinVarID: 11919

Variant1CAID: CA220503

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: A591T

Variant1ClinVarID: 92635

Variant1CAID: CA145876

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: R162I

Variant1ClinVarID:

Variant1CAID: CA355961607

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: M504T

Variant1ClinVarID:

Variant1CAID: CA355964770

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: G197D

Variant1ClinVarID: 554670

Variant1CAID: CA91167598

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: P496L

Variant1ClinVarID: 551675

Variant1CAID: CA91170412

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: G265R

Variant1ClinVarID: 638074

Variant1CAID: CA2802098

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: R489P

Variant1ClinVarID: 1518214

Variant1CAID: CA355964650

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: R105Q

Variant1ClinVarID: 92641

Variant1CAID: CA145881

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: D349Y

Variant1ClinVarID: 638075

Variant1CAID: CA355963146

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: A160D

Variant1ClinVarID:

Variant1CAID: CA355961593

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: A327P

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A