Case#: 28

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.1274T>C

LegacyVariant:

ClinVar: No

CAID: CA414447009

gnomAD:

Case#: 35

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.223C>T

LegacyVariant:

ClinVar: No

CAID: CA340993

gnomAD:

Case#: 36

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.535G>T

LegacyVariant:

ClinVar: No

CAID: CA414440319

gnomAD:

Case#: 12

DiseaseAssertion: NA

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Na

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.434G>A

LegacyVariant:

ClinVar: No

CAID: CA414438950

gnomAD:

Case#: 22

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 19.5%

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.571C>T

LegacyVariant:

ClinVar: No

CAID: CA255340

gnomAD:

Case#: 13

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 3.7%

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.374G>A

LegacyVariant:

ClinVar: No

CAID: CA414437883

gnomAD:

Case#: Odnoczko_Case (male, 74 y/o, in Poland)

DiseaseAssertion: Severe Hemophilia B (only in patients who receive vitamin K antagnoists (VKAs). The authors believe that during VKA therapy, the FIX activity is much lower than that of other vitamin K-dependent clotting factors for cases with this variant.

FamilyInfo: Family history of bleeding diathesis was negative

ParentalTesting:

CasePresentingHPOs: HP:0012233, HP:0031364, HP:0001892

CaseHPOsFreeText: left thigh & buttock hematoma, ecchymosis on extremeties with no mucosal bleeding, bleeding diathesis

CasePreviousTesting: local labaratory blood tests revealed anemia (hemoglobin concentration 8 g/dl; ref. range 14–18 g/dl), prolongation of prothrombin time (PT) with International Normalized Ratio (INR) within the therapeutic range (between 2.0 and 3.0). The proband's activated partial thromboplastin time (APTT) was significantly (>2-folds) prolonged and FIX activity markedly decreased

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#: Mutation found in 4 patients, and in 4 families

DiseaseAssertion: Severe in 2 cases, moderate in the other 2 cases

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858, HP:0003645, HP:0001892

CaseHPOsFreeText: reduced factor IX activity, activated partial thromboplastin time (APTT), normal FVIII clotting activity and bleeding tendency

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Patient HB401 (Hispanic; Male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX Coagulant Activity: 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

Case#: Belvini_Proband_14 (male, Italian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

LegacyVariant:

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Patient 63 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = 3 (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#: Patient 66 (Spanish origin; assumed male)

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Factor IX: C = 30% (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4(F9):c.19A>T (p.Ile7Phe)

LegacyVariant: c.48A>T (p.Ile-40Phe)

ClinVar: 367997

CAID: CA10529708

gnomAD: Filtering AF: 0.0007752 (no homozygotes)

Case#: Patient 72 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = <1 (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: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: P4 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928

CaseHPOFreeText: Low FVIII levels (FVIII:Ag showed a moderate reduction (29.8% ± 1.7, p < 0.01) compared to the WT; FVIII:C undetectable), abnormal blood coagulation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

Gene: F8

Variant: NM_000132.4:c.1730C>A

CAID: CA414911649

gnomAD: Absent/Not Reported

Case#: 37HBT150 (Turkish; assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Reduced factor IX activity (FIX:C: 1.3)

CasePreviousTesting: N/A

Gene: F9

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

LegacyVariant: c.6365 G>T (p.Arg-4Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: HB-125 (assumed male, India)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

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

CaseNotHPOs: None

CasePreviousTesting: None

Gene: F9

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

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Heit_Proband_HB535 (assumed male, AmerIndian from Peru)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

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

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

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

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Mülling_Proband_1 (55 y/o, male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858, HP:0100584, HP:0002094

CaseHPOsFreeText: Reduced factor IX activity (FIX activity: 3%), infective endocarditis, dyspnea

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: Absent

CAID: CA414435437

gnomAD: 0.00002186 in European (non-Finnish) population (highest frequency of variant found in this population)

AdditionalCaseInfo: Patient developed severe bleeding under therapy with phenprocoumon, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors

Case#: Ghanem_Paris 2 (assumed male, from Paris) & Ghanem_ Caen 2 (assumed male, from Caen)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (Paris 2: FIX:C: <1, FIX:Ag: 28, Caen 2: FIX:C: <1

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: 811505

CAID: CA414435537

gnomAD: Highest AF (South Asian population): 0.0004904

Case#: Calgary 15

DiseaseAssertion: Hemophilia B (severity not provided)

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (does not specify severity for probands) "patients from these kindreds have various disease severity, with plasma factor IX activity from < 0.01 U/mL to 0.30 U/mL." "FIX antigen was not available from patients from 6 kindreds, reduced in seven, normal in six, and not available from six."

CaseNotHPOs: None

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#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0001929

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case: Gustafson_II:3

CasePresentingHPOsFreeText: Retrospective review of ophthalmic examination notes was performed in three affected family members (II:2, II:4, and II:6). Information about eye examination, including best corrected visual acuity (BCVA) and dilated fundus examination, kinetic perimetry, and spectral-domain optical coherence tomography (SD-OCT) scans through the fovea were obtained in all three affected patients (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany and Cirrus HD OCT, Carl Zeiss Meditech Inc., Dublin, CA, USA). Full-field electroretinogram (ERG) testing was performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards [ 4 ] in the two sisters (II:2 and II:4) but was not performed in the second cousin (II:6).

CasePreviousTesting: WES

CaseGenotypingMethod: Whole exomes of three affected (II:2, II:4 and II:6) and to unaffected family members (I:6, II:3) were sequenced using Agilent Sure Select V1 probes (Agilent Technologies, Inc., Santa Clara, CA, USA) and Illumina HiSeq 2500 (Illumina, San Diego, CA, USA). Whole genomes of family members II:2, II:3, II:4, II:6, and I:6 were sequenced at more than 30X depth using Illumina HiSeq X (Illumina,). Segregation of substitution mutations and small deletions were tested by dideoxy sequencing

Variant: c.226C>T (p.Arg76*)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Ashkenazi Jewish

PreviouslyPublished:

VariantEvidence:

Case: Gustafson_II:1, female, 60 years old

CasePresentingHPOsFreeText: Retrospective review of ophthalmic examination notes was performed in three affected family members (II:2, II:4, and II:6). Information about eye examination, including best corrected visual acuity (BCVA) and dilated fundus examination, kinetic perimetry, and spectral-domain optical coherence tomography (SD-OCT) scans through the fovea were obtained in all three affected patients (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany and Cirrus HD OCT, Carl Zeiss Meditech Inc., Dublin, CA, USA). Full-field electroretinogram (ERG) testing was performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards [ 4 ] in the two sisters (II:2 and II:4) but was not performed in the second cousin (II:6)

CasePreviousTesting: WES

CaseGenotypingMethod: Whole exomes of three affected (II:2, II:4 and II:6) and to unaffected family members (I:6, II:3) were sequenced using Agilent Sure Select V1 probes (Agilent Technologies, Inc., Santa Clara, CA, USA) and Illumina HiSeq 2500 (Illumina, San Diego, CA, USA). Whole genomes of family members II:2, II:3, II:4, II:6, and I:6 were sequenced at more than 30X depth using Illumina HiSeq X (Illumina,). Segregation of substitution mutations and small deletions were tested by dideoxy sequencing

Variant: c.226C>T (p.Arg76*)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Ashkenazi Jewish

PreviouslyPublished:

VariantEvidence:

Case: Shamieh_FamilyC_II:3; CIC01225

CasePresentingHPOsFreeText: Rod-cone dystrophy, Each subject underwent an ophthalmic exami- nation with clinical assessment as previously described. The three affected individuals with KIZ variants in this study were all diagnosed with RCD in their late teens on the basis of night blindness followed by changes in mid- peripheral visual fields and undetectable responses in a full-field electroretinogram by approximately 35 years of age.

CasePreviousTesting: No mention of previous testing

CaseGenotypingMethod: screening of coding and flanking exonic regions of KIZ by direct Sanger sequencing

Variant: compound heterozygous for the c.52G>T (p.Glu18) and c.119_122delAACT (p.Lys40Ilefs14) variants.

ClinVarID: or CAID: c.52G>T (CA151550) , c.119_122delAACT (CA151553)

gnomAD: allele frequency = 0.00009237 for the c.119_122delAACT variant, c.52G>T variant is absent from gnomAD v2.1.1

AddCaseInfo: Cosegregation analysis revealed that the father was heterozygous for the nonsense mutation and the mother was heterozygous for the frameshift deletion

Case#: P10-GR, F, Age of Report: 63 y.o., Ethnicity: Greece.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000613 (Photophobia), HP:0200070 (Peripheral retinal atrophy/diffuse outer retinal atrophy), HP:0025010 (Foveal atrophy), HP:0500087 (Peripapillary atrophy), HP:0030329 (Retinal thinning), HP:0008619 (Bilateral sensorineural hearing impairment/bilateral hearing impairment/moderate SNHL)

CaseHPOFreeText: P10-GR is a 63 year-old female with adulthood-onset RP. She is the third offspring of a non-consanguineous marriage with no family history of RP or hearing loss (Fig.1g).

She reported night blindness since the age of 25 years with subsequent visual field constriction around the age of 35 and recent onset of photophobia. Her BCVA was 0.16 D in the right eye and 0.125 D in the left eye and she was pseudophakic. Fundoscopy revealed the presence of diffuse outer retinal atrophy with intraretinal pigment migration in the mid- and far-periphery along with foveal and peripapillary atrophy and vessel attenuation. FAF imaging showed areas of hypo-autofluorescence in the periphery, around the optic disc and in the fovea corresponding to the areas of retinal atrophy. SD-OCT showed retinal thinning with atrophy of outer retinal layers and foveal RPE loss (Fig. 2f, Table 2). The patient reported bilateral hearing impairment since the age of 58 years. Audiometry confirmed the presence of moderate SNHL with a flat audiogram and a PTA of 50 dB (Fig. 3).

CaseNotHPOs: N/A..

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_021831.6:c.883G>A (p.Asp295Asn). Variant 2: NM_021831.6:c.316A>G (p.Met106Val ).

ClinVar: Variant 1: 242932. Variant 2: N/A.

CAID: Variant 1: CA10584033. Variant 2: CA346170014.

gnomAD: Variant 1: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4. Variant 2: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053502-A-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Molecular analysis identified two compound heterozygous variants in AGBL5: c.883G>A, p.(Asp295Asn) and c.316A>G, p.(Met106Val), that were shown to be in trans, since the unaffected daughter of the patient only carries the c.883G>A, p.(Asp295Asn) (Fig. 1g, Table 1).

CasePMIDs: N/A.

Case: Jauregui_Case3

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.226C>T (p.R76X)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Male. Caucasian, 21 years old

PreviouslyPublished:

VariantEvidence:

Case: Jauregui_Case2

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.226C>T (p.R76X)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Male. Caucasian, 60 years old

PreviouslyPublished:

VariantEvidence:

Case: Jauregui_Case1

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.119_122delAACT (p.K40IfsX14)

ClinVarID: or CAID: CA151553

gnomAD: allele freq. of 0.00009237 in the European (non-finnish) population

AddCaseInfo: Male. Caucasian, 56 years old

PreviouslyPublished:

VariantEvidence:

Case: Lin_FamilyB_II:1

CasePresentingHPOsFreeText: Ophthalmic examination notes were retrospectively reviewed in patients. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT) scans through the fovea, and short-wavelength fundus autofluorescence (SW-AF, 488 nm), were obtained in all four affected patients with Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Full-field electroretinogram (ERG) testing was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients in this study exhibited chorioretinal phenotypes characteristic of RP (Figure 1). All patients initially presented with night blindness followed by progressive constriction of their visual field. ERG recordings were collected from three patients (A-II:2, B-II:1, and D-II:5) (Figure 3). For A-II:2 at 60 years of age and D-II:5 at age 37 years of age, ERG rod responses of the right eyes were almost undetectable.

CasePreviousTesting: WES

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either whole exome sequencing (WES, A-II:2, B-II:1, and D-II:5)

Variant: c.119_122delAACT (p.Lys40llefsTer14)

ClinVarID: or CAID: CA151553

gnomAD: allele frequency of 0.00009237 in the European (non-Finnish) population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Lin_FamilyD_II:5

CasePresentingHPOsFreeText: Ophthalmic examination notes were retrospectively reviewed in patients. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT) scans through the fovea, and short-wavelength fundus autofluorescence (SW-AF, 488 nm), were obtained in all four affected patients with Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Full-field electroretinogram (ERG) testing was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients in this study exhibited chorioretinal phenotypes characteristic of RP (Figure 1). All patients initially presented with night blindness followed by progressive constriction of their visual field. ERG recordings were collected from three patients (A-II:2, B-II:1, and D-II:5) (Figure 3). For A-II:2 at 60 years of age and D-II:5 at age 37 years of age, ERG rod responses of the right eyes were almost undetectable.

CasePreviousTesting: WES

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either whole exome sequencing (WES, A-II:2, B-II:1, and D-II:5)

Variant: c.226C>T (p.Arg76Ter)

ClinVarID: or CAID: CA151548

gnomAD: allele frequency of 0.001173 in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Family#: RP19

PresentingHPOs: HP:0007642, HP:0030824 (Congenital stationary night blindness, Mizuo-Nakamura phenomenon)

PresentingHPOsFreeText: Diffuse gray discoloration of the fundus, scotopic ERG showed a significantly reduced rod response (in selected individuals analyzed)

FamilyNotHPOsFreeText: During fundoscopy of the individuals IV-3 and V-1, no bone spicule deposits were observed in the fundus.

CountryOrigin: Pakistan, central region of Punjab province

Family#PreviousTesting: None

Family#Method1: Homozygosity mapping

Family#Method2: Sequencing

Family#GenotypingMethod: Linkage: Six affected family members were analyzed by whole-genome SNP analysis, which showed homozygosity for a 15.2 Mb region on chromosome 13q34. Using fluorescently labeled microsatellite markers to analyze all available family members, the critical region was refined to a 5-Mb region between D13S1315 (position 109.1 Mb) at the centromeric side and 13qter (position 114.1 Mb). All eight affected individuals were homozygous for this chromosomal interval (Figure 1). A maximum two-point LOD score of 5.1 for marker D13S1295 at theta 0 was determined.

All seven coding exons and flanking intronic sequences of GRK1 were sequenced in affected family members IV-1, V-5, and V-11. The segregation of a novel mutation in the family and the frequency of the identified mutation in the Pakistani population were determined by StuI RFLP analysis.

Affected: 8

Unaffected: 14

PublishedLOD: Maximum two-point LOD score of 5.1 for marker D13S1295 at theta 0.

ProbandLabel: RP19, IV-1

Variant: NM_002929.3(GRK1):c.614C>A (p.Ser205Ter) (homozygous)

ClinVar: 870430

CAID: CA388824706

gnomAD: Not in gnomAD

FamilyAddInfo: All parents, as well as several unaffected siblings, were heterozygous carriers of the variant. Eight unaffected individuals were homozygous for the wild-type sequence. In two branches of the family, (IV6/IV7, IV8/IV9, and their children) the parents are first cousins.

Case#: RP19, IV-1

CaseHPOs: HP:0007642, HP:0030824 (Congenital stationary night blindness, Mizuo-Nakamura phenomenon)

CaseHPOsFreeText: Diffuse gray discoloration of the fundus, scotopic ERG showed a significantly reduced rod response (in selected individuals analyzed)

CaseNotHPOsFreeText: During fundoscopy of the individuals IV-3 and V-1, no bone spicule deposits were observed in the fundus.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: All seven coding exons and flanking intronic sequences of GRK1 were sequenced in affected family members IV-1, V-5, and V-11.

Variant: NM_002929.3(GRK1):c.614C>A (p.Ser205Ter) (homozygous)

ClinVar: 870430

CAID: CA388824706

gnomAD: Not in gnomAD

Case#: Uttarilli Patient 6, male, 4yo at presentation

DiseaseAssertion: MPS1, Hurler-Scheie

FamilyInfo: non-consanguineous

CasePresentingHPOs: HP:0007957, HP:0000280, HP:0000943, HP:0002240, HP:0001744

CaseHPOFreeText: IDUA enzyme activity=0 (reference = 11–26 nmol/h/mg)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of all exons of IDUA and IDS genes and bidirectional sequencing

PreviouslyPublished:

Variant: [c.223G>A] [p.Ala75Thr]; [c.895G>T] [p.Glu299*]

CAID: CA356994; CA355962511

SupplementalData: n/a

Case#: Patient 25, male, 7 months (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomyopathy, dysostosis multiplex, global developmental delay, hepatomegaly, inguinal hernia, skeletal abnormalities, splenomegaly, recurrent respiratory infections (HP:0007957, HP:0000256, HP:0001638, HP:0000943, HP:0001263, HP:0002240, HP:0000023, HP:0002652, HP:0001744, HP:0002205)

CaseHPOFreeText: Global dyskinesia

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.R619X)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1855C>T (p.R619X)

Variant2ClinVarID: 280976

Variant2CAID: CA2802455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 20, male, 8 years (age at presentation).

DiseaseAssertion: MPS1-H/S

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

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomyopathy, dystosis multiplex (HP:0007957, HP:0000256, HP:0001638, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1469T>C (p.L490P)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12, female, 6 months (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, intellectual disability, recurrent respiratory infections, splenomegaly, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0010864, HP:0002205, HP:0001744, HP:0001537)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.783delC (p.His262Thrfs*55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

Variant2: c.783delC (p.His262Thrfs*55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 26, male, 1 year (age at presentation).

DiseaseAssertion: MPS1-H

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

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, intellectual disabilities, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0010864, HP:0001744)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.R619X)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1855C>T (p.R619X)

Variant2ClinVarID: 280976

Variant2CAID: CA2802455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 47, female, Han origin, 4 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0001387, HP:0001433, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hernia (HP:0001263, HP:0000256, HP:0011369, HP:0100790)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.9 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: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

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

Variant2ClinVarID: 556406

Variant2CAID: CA355961718

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 57, female, Han origin, 2 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness (HP:0001387)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1262T>C (p.L421P)

Variant1ClinVarID: 1328979

Variant1CAID: CA355963724

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#: Patient 27, female, Han origin, 9 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/S

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Hernia (HP:0001263, HP:0000256, HP:0100790)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 3.4 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.98A>C (p.H33P)

Variant1ClinVarID: N/A

Variant1CAID: CA355945475

Variant2: c.1402+2T>G

Variant2ClinVarID: 553131

Variant2CAID: CA355964392

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 21, female, Han origin, 10 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula (HP:0001263, HP:0000256, HP:0011369)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.536C>G (p.T179R)

Variant2ClinVarID: 556358

Variant2CAID: CA355961718

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 36, female, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0000256, HP:0001387, HP:0001433, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Mongolian macula, Hernia, (HP:0001263, HP:0011369, HP:0100790)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.159C>A (p.C53X)

Variant1ClinVarID: 1458768

Variant1CAID: N/A

Variant2: c.1037T>G (p.L346R)

Variant2ClinVarID: 11927

Variant2CAID: CA256128

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 43, male, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly (HP:0001263, HP:0000256)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.300-3C>G

Variant1ClinVarID: 551563

Variant1CAID: CA549265042

Variant2: c.530dupT (p.Glu178ArgfsTer5) (Paper refers to the variant as c.531dupT, there is a typo in the article where all duplication variants are one base pair off)

Variant2ClinVarID: N/A

Variant2CAID: CA2586973520

AdditionalVariants: c.1037T>G (p.L346R)

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 10, born in 2010 (paper published in 2017), 6 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 60 ng/mol (26 weight matched enzyme reference assay)

CaseUrineGAGs: 0.29 DS/CS

CaseERT: Yes

CaseBMT: Yes, Cord

Variant1: c.1598C>G (p.P533R)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.1598C>G (p.P533R)

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 14, born in 1998 (paper published in 2017), 19 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding, cataract (HP:0007957, HP:0000518)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy (HP:0000488)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 31.4 ng/mol (60.7 weight matched enzyme reference assay)

CaseUrineGAGs: 0.60 DS/CS

CaseERT: No

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.979G>C (p.A327P)

Variant2ClinVarID: 167190

Variant2CAID: CA234128

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 24, born in 2009 (paper published in 2017), 8 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Cataract, retinopathy (HP:0000518, HP:0000488)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 48.88 ng/mol (48.75 weight matched enzyme reference assay)

CaseUrineGAGs: 0.28 DS/CS

CaseERT: Yes

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 7, born in 2005 (paper published in 2017), 16 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 62.57 ng/mol (34.3 weight matched enzyme reference assay)

CaseUrineGAGs: 0.59 DS/CS

CaseERT: No

CaseBMT: Yes, Cord

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.386-2A>G

Variant2ClinVarID: 222994

Variant2CAID: CA356991

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2, born in 2000 (paper published in 2017), 18 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 28 ng/mol (38 weight matched enzyme reference assay)

CaseUrineGAGs: 0.36 DS/CS

CaseERT: No

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.979G>C (p.A327P)

Variant2ClinVarID: 167190

Variant2CAID: CA234128

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 109, Far East district of the Russian Federation

DiseaseAssertion: MPS1, Severe

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IdA activity in DBS=0,01 leukocytes, severe phenotype, hyperexcretion of urine heparan and dermatan sulfate

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Electrophoresis of urine GAGs and measurement of lysosomal enzyme activity in peripheral blood leukocytes or DBSs were performed for all patients with suspected MPS I

GenotypingMethod: The 14 exons and exon–intron boundaries of the IDUA gene were amplified from DNA samples. Sanger sequencing of each one of the 14 exons was performed. PCR products containing mutations were re-sequenced in both directions. The mutations were further confirmed where possible by restriction analysis (data not shown).

PreviouslyPublished:

Variant: NM_000203.5:c.[208C>T];[1029C>A]

ClinVar: 222997

CAID: CA356984

SupplementalData: n/a

Case#: Patient 108, Central district of the Russian Federation

DiseaseAssertion: MPS1, Severe

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IdA activity in DBS=0,01 DBS, severe phenotype, hyperexcretion of urine heparan and dermatan sulfate

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Electrophoresis of urine GAGs and measurement of lysosomal enzyme activity in peripheral blood leukocytes or DBSs were performed for all patients with suspected MPS I

GenotypingMethod: The 14 exons and exon–intron boundaries of the IDUA gene were amplified from DNA samples. Sanger sequencing of each one of the 14 exons was performed. PCR products containing mutations were re-sequenced in both directions. The mutations were further confirmed where possible by restriction analysis (data not shown).

PreviouslyPublished:

Variant: NM_000203.5:c.[208C>T];[1029C>A]

ClinVar: 222997

CAID: CA356984

SupplementalData: n/a

Case#: Infant 3

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.18 nmol/h/mg; normal range, 6-71.4 nmol/h/mg

CaseUrineGAGs: 25.49 mg/mmol creatinine; normal ranges, 0-53 mg/mmol creatinine

CaseERT: N/A

CaseBMT: N/A

Variant1: c.900G>A (p.A300=) homozygous for this variant + homozygous with a 2nd variant

Variant1ClinVarID: 1107522

Variant1CAID: CA438057521

Variant2: c.904C>A (p.P302T) homozygous for this variant + the first variant

Variant2ClinVarID: 1067236

Variant2CAID: CA355962529

AdditionalVariants: N/A

ParentalGenotype: c.900G>A (homozygous); c.904C>A (homozygous)

PreviouslyPublished N/A

Case#: Patient 8: Enrolled in study at 12.3 years, Female, onset at 1.5 years, diagnosed at 7.2 years, ERT started 9.4 years DiseaseAssertion:MPS1 H-S FamilyInfo: Consanguinity No CasePresentingHPOs:Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), , CaseHPOFreeText: CaseNotHPOs: Macrocephaly (HP:0000256), CaseNotHPOFreeText: CaseEnzymeAssay: CaseUrineGAGs: 2.05(min)-8.87(max) mg GAG/mmol creatinine while on ERT CaseERT: Laronidase dose-optimization trial : standard regimen – 0.58 mg/kg/week; biweekly regimen – 1.2 mg/kg every two weeks CaseBMT:Nil Variant1: IDUA W402X Variant1ClinVar ID: 11908 Variant1CAID: CA220498 Variant2:P533R Variant2ClinVarID:11910 Variant2CAID:CA256112 AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

Case#: Patient 87, Turkey

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguineous parents

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.956_972+9delinsTA

Variant1ClinVarID: N/A

Variant1CAID: CA3271845954

Variant2: c.956_972+9delinsTA

Variant2ClinVarID: N/A

Variant2CAID: CA3271845954

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 59, Poland

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.656G>A (p.G219E)

Variant1ClinVarID: 4078973

Variant1CAID: CA355962006

Variant2: c.917G>T (p.W306L)

Variant2ClinVarID: 2203497

Variant2CAID: CA355962596

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 29, Italy

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: c.878_889dup

Variant2ClinVarID: 550382

Variant2CAID: CA2802114

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 27, Italy

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1189+5G>A

Variant1ClinVarID: 551848

Variant1CAID: CA658823290

Variant2: c.46_57del

Variant2ClinVarID: 92643

Variant2CAID: CA220509

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished Yes - PMID: 23210910

Case#: Patient 35, Italy

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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.398_403del (p.Met133_Gly134del)

Variant2ClinVarID: 863830

Variant2CAID: CA2801912

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 49, Poland

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.878_889dup (p.Thr293_Tyr296dup)

Variant1ClinVarID: 550382

Variant1CAID: CA2802114

Variant2: c.1181_1189dup (p.Ala394_Leu396dup)

Variant2ClinVarID: 3720561

Variant2CAID: CA549264540

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 32, Italy

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1225G>A (p.G265R)

Variant2ClinVarID: 1084956

Variant2CAID: CA91169920

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 82, Turkey

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1469T>C (p.L490P)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, Italy

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1603C>T (p.L535F)

Variant2ClinVarID: 638076

Variant2CAID: CA355865038

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 65, Spain

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: c.1154C>G (p.P385R)

Variant2ClinVarID: 556024

Variant2CAID: CA355963438

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 22 (see Table 2), 37 weeks (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Homozygous twin of Patient 23 (see Table 2)

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1598C>G (p.P533R)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.1598C>G (p.P533R)

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10 (see Table 2), Gestational age not available

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.653T>C (p.L218P)

Variant2ClinVarID: 222995

Variant2CAID: CA:356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 30 (see Table 2), 40 weeks (Gestational age)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.474-2A>G (new nomenclature: c.386-2A>G)

Variant1ClinVarID: 222994

Variant1CAID: CA356991

Variant2: c.1148G>A (p.R383H)

Variant2ClinVarID: 558189

Variant2CAID: CA:2802205

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 14 (see Table 2), 41 weeks, 1 day (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Inguinal hernia (HP:0000023)

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1100C>A (p.A367E)

Variant1ClinVarID: 3769492

Variant1CAID: CA355963330

Variant2: c.1650del117 (c.1650_1766del)

Variant2ClinVarID: N/A

Variant2CAID: CA3250142363

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 15 (see Table 2), 38 weeks, 1 day (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Inguinal hernia (HP:0000023)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.23 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.494-1G > A

Variant1ClinVarID: 557942

Variant1CAID: CA355961634

Variant2: c.494-1G > A

Variant2ClinVarID: 557942

Variant2CAID: CA355961634

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#:Patient Sample unique ID 2

DiseaseAssertion:MPS type I-Hurler children

FamilyInfo:None

CasePresentingHPOs:Obstructive sleep apnea, HP:0002870

CaseHPOFreeText:None

CaseNotHPOs:None

CaseNotHPOFreeText:None

CaseEnzymeAssay:None

CaseUrineGAGs: Tested but amounts not reported

CaseERT:No

CaseBMT:Hematopoietic stem cell transplantation

Variant1:c.1205G>A

Variant1ClinVarID:11908

Variant1CAID:CA220498

Variant2:c.1205G>A

Variant2ClinVarID:11908

Variant2CAID:CA220498

AdditionalVariants:None

ParentalGenotype:None provided

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: R383H

Variant1ClinVarID: 558189

Variant1CAID: CA2802205

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: R628P

Variant1ClinVarID: 1064675

Variant1CAID: CA2802464

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: R619G

Variant1ClinVarID: 11924

Variant1CAID: CA256125

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: A361T

Variant1ClinVarID: 92624

Variant1CAID: CA145865

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: Q380R

Variant1ClinVarID: 550799

Variant1CAID: CA2802202

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: G219E

Variant1ClinVarID:

Variant1CAID: CA355962006

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: D349N

Variant1ClinVarID: 92623

Variant1CAID: CA220497

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: M133I

Variant1ClinVarID:

Variant1CAID: CA91166179

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Functional assay variant with a clinical significance of being a VUS.

DiseaseAssertion: MPS-I

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.1091C>A (p.T364K)

Variant1ClinVarID: 2961353

Variant1CAID: CA355963315

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Functional assay variant with a clinical significance of being a VUS.

DiseaseAssertion: MPS-I

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.1861C>G (p.R621G)

Variant1ClinVarID: 444626

Variant1CAID: CA2802458

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Functional assay variant with a clinical significance of pathogenic.

DiseaseAssertion: MPS-I

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.1139A>G (p.Q380R)

Variant1ClinVarID: 550799

Variant1CAID: CA2802202

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Functional assay variant with a clinical significance of pathogenic.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 52, 2 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections (HP:0000280, HP:0001433, HP:0007957, HP:0002719)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.395C>T (p.Leu132Pro) in the article - incorrect variant. Possible correct nomenclature is c.395T>C (p.Leu132Pro) or c.394C>T (p.Leu132=)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.1839delT (p.Val614Serfs*7)

Variant2ClinVarID: N/A

Variant2CAID: CA2586965995

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 59, 8 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of Patient 58

CasePresentingHPOs: Coarse facial features, corneal clouding, dysostosis multiplex (HP:0000280, HP:0007957, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.8% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1044C>G (p.Asn348Lys)

Variant1ClinVarID: 557870

Variant1CAID: CA2802172

Variant2: c.1598C>G (p.Pro533Arg)

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 61, 1 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, intellectual disability (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.5% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1195_1197del (p.Glu399del)

Variant1ClinVarID: 2498386

Variant1CAID: CA549264677

Variant2: c.1249_1275del (p.Thr417_His425fs*55)

Variant2ClinVarID: 556156

Variant2CAID: CA658823291

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 13, 9 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding (HP:0000280, HP:0001433, HP:0002828, HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.532G>A (p.Glu178Lys)

Variant1ClinVarID: 2203495

Variant1CAID: CA355961709

Variant2: c.532G>A (p.Glu178Lys)

Variant2ClinVarID: 2203495

Variant2CAID: CA355961709

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8, 3 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0100790)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.1% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.436A>T (p.Lys146Ter)

Variant1ClinVarID: N/A

Variant1CAID: CA355961453

Variant2: c.436A>T (p.Lys146Ter)

Variant2ClinVarID: N/A

Variant2CAID: CA355961453

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 27, 4 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, dysostosis multiplex (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1249_1275del (p.Thr417_His425del)

Variant1ClinVarID: 556156

Variant1CAID: CA658823291

Variant2: c.1249_1275del (p.Thr417_His425del)

Variant2ClinVarID: 556156

Variant2CAID: CA658823291

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 42, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0002828, HP:0007957, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.1% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1855C>T (p.Arg619Ter)

Variant1ClinVarID: 280976

Variant1CAID: CA2802455

Variant2: c.1855C>T (p.Arg619Ter)

Variant2ClinVarID: 280976

Variant2CAID: CA2802455

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 37, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0002828, HP:0007957, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 4.8% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1373T>C (p.Leu458Pro)

Variant1ClinVarID: N/A

Variant1CAID: CA355964255

Variant2: c.1373T>C (p.Leu458Pro)

Variant2ClinVarID: N/A

Variant2CAID: CA355964255

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 28, 8 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, dysostosis multiplex (HP:0000280, HP:0001433, HP:0007957, HP:0000943)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1273delC (p.His425Thrfs*15)

Variant1ClinVarID: 3391381

Variant1CAID: CA2586965976

Variant2: c.1273delC (p.His425Thrfs*15)

Variant2ClinVarID: 556156

Variant2CAID: CA2586965976

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 50, 2 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, hernia (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.238G>T (p.Val80Phe)

Variant1ClinVarID: N/A

Variant1CAID: CA355946451

Variant2: c.784delC (p.His262Thrfs*55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, 1 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of patient 11

CasePresentingHPOs: Coarse facial features, recurrent infections, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.531C>G (p.Phe177Leu)

Variant1ClinVarID: 2432729

Variant1CAID: CA2801983

Variant2: c.531C>G (p.Phe177Leu)

Variant2ClinVarID: 2432729

Variant2CAID: CA2801983

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 30, 8 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1373T>C (p.Leu458Pro)

Variant1ClinVarID: N/A

Variant1CAID: CA355964255

Variant2: c.1373T>C (p.Leu458Pro)

Variant2ClinVarID: N/A

Variant2CAID: CA355964255

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 51, 2 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, dysostosis multiplex (HP:0000280, HP:0001433, HP:0002828, HP:0000943)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.265G>C in the article - incorrect variant but unknown what the correct nomenclature is. Could be c.265C>G (p.Arg89Gly) or c.266G>C (p.Arg89Pro)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.779C>T (p.Ser260Phe)

Variant2ClinVarID: 3895951

Variant2CAID: CA355962251

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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: 0.9 ± 0.1 nmol/mg/h IDUA activity at 37 °C

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: c.1598C>G (p.P533R)

ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A