Case#: N/A

DiseaseAssertion: Severe/Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0001929

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#: 15

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 2.6%

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.781T>C

LegacyVariant:

ClinVar: No

CAID: CA414443378

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 1.8%

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:

LegacyVariant: NM_000133.3:c.880C>T

ClinVar: No

CAID: CA255344

gnomAD:

Case#: 4

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.520G>C

LegacyVariant:

ClinVar: No

CAID: CA414439517

gnomAD:

Case#: 32

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.1306G>A

LegacyVariant:

ClinVar: No

CAID: CA414447233

gnomAD:

Case#: 23

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.1193G>A

LegacyVariant:

ClinVar: No

CAID: CA414446384

gnomAD:

Case#: 3

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.128G>A

LegacyVariant:

ClinVar: No

CAID: CA414435539

gnomAD:

Case#: 16

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 12%

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.881G>A

LegacyVariant:

ClinVar: No

CAID: CA255368

gnomAD:

Case#: 10

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 2.5%

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.571C>T

LegacyVariant:

ClinVar: No

CAID: CA255340

gnomAD:

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.68T>C (p.Leu23Pro)

ClinVar: Absent

CAID: CA414434403

gnomAD: Absent/NotReported

Case#: N/A

DiseaseAssertion: Hemophilia B (severity not specified)

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: Not provided

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.86C>T (p.Thr29Ile)

ClinVar: Absent

CAID: CA414434494

gnomAD: Absent/NotReported

Case#: Belvini_Proband_13 (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.110C>A (p.Ala37Asp)

ClinVar: Absent

CAID: CA414435430

gnomAD: Absent/Not Reported

Case#: Belvini_Proband_16 (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.135G>C (p.Lys45Asn)

ClinVar: Absent

CAID: CA414435574

gnomAD: Absent/Not Reported

Case#: Patient D (assumed male)

DiseaseAssertion: Severe, Sporadic Hemophilia B

FamilyInfo: Patient D's mother is heterozygous and she has had a second, affected son. the maternal grandmother's DNA was also heterozygous

ParentalTesting: Mother was heterozygous for the variant

CasePresentingHPOs: HP:0011858

CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1; FIX:Ag:41)

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#: P1 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

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

CaseHPOFreeText: Low FVIII levels (significant decrease in FVIII:C 1.4% ± 0.2 and FVIII:Ag levels 3.9% ± 0.2), prolonged bleeding after surgery, mild bleeding tendency

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.320T>A

CAID: CA414920017

gnomAD: Absent/Not Reported

Case Info: P6 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928, HP:0001892

CaseHPOFreeText: Low FVIII levels (in vitro results were similar to the WT control and led to a normal specific activity (82.7% ± 9.0)), abnormal blood coagulation, 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 and in silico analysis were also performed.

Gene: F8

Variant: NM_000132.4:c.6095T>C

CAID: CA414904631

gnomAD: Absent/Not Reported

Case#: 014 (AD); Polish origin

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CasePresentingHPOsFreeText: FIX:C : 2; FIX:Ag : 65

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.138G>T (p.Arg46Ser)

ClinVar: Absent/Not Reported

CAID: CA414435596

gnomAD: Absent/Not Reported

Case#: Guo_Family 2_Proband 1 (Chinese, assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:Ag: 1.6%, FIX:C: 2.1%

CaseNotHPOs: 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#: IG13 (Italian, assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

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

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

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

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

ClinVar: Absent

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: Awidi_Variant_1 (9 patients, 2 families)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Positive family history

ParentalTesting: Positive family history

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

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#: Heit_Proband_HB541 (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.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Miller_Proband 2 (male)

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.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Lin_Patient 3 (assumed male, Chinese origin)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1 ; FIX:Ag: 38)

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#: Quadros_Proband_ ID_#2

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.112A>C (p.Asn38His)

ClinVar: Absent

CAID: CA414435439

gnomAD: Absent/Not Reported

Case#: Liu_Proband_316 (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.82T>G (p.Cys28Gly)

ClinVar: Absent

CAID: CA414434482

gnomAD: Absent/Not Reported

Case: Shamieh_FamilyA_II:2; CIC00173

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: At a time when next-generation sequencing (NGS) approaches were not commonly used, index subject CIC00173 II.2 (family A, Figure 1) was excluded upon screening by microarray analysis and direct Sanger sequencing for known mutations in EYS and C2orf71 (a major and a minor gene, respectively, implicated in RCD). 11,12 Because exon ORF15 in RPGR (MIM 312610) is not targeted by existing NGS panels,13 we also analyzed it by Sanger sequencing but found no pathogenic variant. Subsequently, we performed targeted NGS on the index subject’s DNA by using a panel of 120 genes previously found to carry mutations in retinal diseases (this panel was modified and improved since our previous study). This survey did not reveal any pathogenic variant, and we therefore proceeded to WES.

CaseGenotypingMethod: In the present study, we applied whole-exome sequencing (WES) to five members (including one affected by RCD) of a consanguineous family (family A).

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

ClinVarID: or CAID: CA151548

gnomAD: Variant present at a frequency of 0.006316 in the Ashkenazi Jewish (9658 alleles tested) and 0.001173 in the Latino populations.

AddCaseInfo: consanguineous family. Both parents and the sister of the proband each carried one copy of the variant, but none were affected with RCD. To investigate whether the stop variant represents a founder alteration, we performed haplotype analysis for each of the index subjects (CIC00173 II.2 from family A) and CIC01611 II.1 from family B) by selecting 11 microsat- ellite DNA markers flanking the KIZ locus. 25 These markers were distributed over a physical distance of z7.38 Mb, cor- responding to z10.5 cM (genetic distance according to Marshfield genetic maps). Both subjects were found to share a common haplotype of five polymorphic microsa- tellites (DS20S54, DS20S63, DS20S190, DS20S868, and DS20S180) flanking KIZ and spanning z1.75 cM (1.18 Mb) (Figure 1). This result suggests that c.226C>T (p.Arg76*) is most likely a founder mutation causing autosomal-recessive RCD in the southern European population

VariantEvidence: We detected a homozygous nonsense mutation, c.226C>T (p.Arg76*), in the third exon of KIZ, coding for centrosomal protein kizuna (KIZ)

Case#: IV-2, M, Age of Diagnosis: 33 y.o., Ethnicity: Arab-Muslim origin.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0100014 (Epiretinal membrane), HP:0001696 (Situs inversus totalis), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous parents.

Proband was noted to find have visual acuity of 0.2 in the right eye (RE) and 0.4 in the left eye (LE), and his Goldmann visual fields were constricted to 10°–12° with the V4e target.

Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D). Neither photopic nor scotopic electroretinogram (ERG) responses were detectable.

Audiometric testing was within normal limits in all three siblings, and computed-tomography imaging revealed full thoracic and abdominal situs inversus in individuals IV-1 and IV-2 but normal situs composition (situs solitus) in individual IV-3.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Homozygosity mapping.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_012106.4:c.101-1G>C.

ClinVar: 65473.

CAID: CA10575604.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: "When she was 36 years old, his older sister (IV-1; Figure 1A) had severely impaired vision: she could detect hand motion in the RE and had bare light perception in the LE. There were no significant refractive errors. Mild posterior subcapsular cataracts were present, and fundoscopy revealed optic-disc pallor, mild-to-moderate bone-spicule-like pigmentation in the midperiphery, and attenuated retinal blood vessels, all typical signs of RP. Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D)."

Case: Shamieh_CIC07875

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.226C>T (p. R76*) homozygous

ClinVarID: or CAID: CA151548

gnomAD: 0.001173 frequecny in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#: 12DG0507_III:2, M, Age: N/A., Ethnicity: N/A.

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

CaseHPOFreeText: N/A.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.826C>T (p.Arg276Trp).

ClinVar: 242933.

CAID: CA10584034.

gnomAD: Frequency: 0.000002470. Link: https://gnomad.broadinstitute.org/variant/chr2-27055171-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband had two affected brothers.

CasePMIDs: N/A.

Case#: Patient 4, 64 years (at report), female

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

CaseHPOsFreeText: Relatively late onset of disease (first symptoms around age 30 years). 1.7 LogMAR in both eyes. Refractive error was −2.00 sph in both eyes. Fundus exam showed a tigroid aspect with vessel thinning, macular atrophy, and optic pallor. Flash full-field ERG recordings showed a non-detectable response for the photopic component and a reduced response for the scotopic response. MfERG response was markedly reduced but still detectable in both eyes, presenting a residual foveal cone function. OCT macular scan showed a marked foveal thinning with advanced photo-receptor layer disruption (Fig 5)

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: c.321G>A (p.Trp107Ter), homozygous

ClinVar: N/A

CAID: CA356373812

gnomAD: The variant is absent in gnomAD.

VariantEvidence: Structural analysis of p.Trp107Ter suggested that truncation of the protein sequence after residue W107 would break up helix α3, resulting in the absence of the C-terminal part of α3, β5, α4, β6, and α5. Missing structural elements β5, β6, and α5 would most probably result in failure to fold correctly or bind GTP/GDP causing degradation.

Case#: Patient 2, male, 33 (at report), 6 years old at onset

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

CaseHPOsFreeText: BCVA LogMAR 1 for both eyes, refractive error −4.25 sph −2.00 cyl/180° D in right eye and −4.00 sph −2.50 cyl/30° D in left eye. The fundus exam showed normal optic disk, signs of foveal atrophy, and “salt and pepper” peripheral retinopathy. Fundus autofluorescence revealed a dark central area due to the absence of the RPE surrounded by an unusual hyperfluorescent perifoveal ring in both eyes while infrared retinography showed foveal atrophy. OCT imaging revealed a marked reduction of the foveal thickness associated with a photoreceptor layer disruption (Figure 3). Goldmann visual field test showed central scotoma with a mild peripheral constriction.

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: c.37del (p.Leu13Ter) homozygous

ClinVar: N/A

CAID: CA2860243

gnomAD: The highest MAF in gnomAD v2.1.1 is 0.00003019 in European non-Finnish (no homozygotes in any population)

VariantEvidence: The variant would either result in nonsense-mediated mRNA decay, or retain few of the structural elements required for correct folding, causing degradation.

CaseAddInfo: Patient 3 is the affected sister of Patient 2. She is affected but has a milder phenotype. The father of these individual is unaffected and heterozygous for the variant. No details are provided about the mother.

Case#: P6-PS, F, Age of Report: 26 y.o., Ethnicity: Palestinian origin.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0011505 (Cystoid macular edema), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0008542 (Low-frequency hearing loss), HP:0012713 (Moderate hearing impairment),

CaseHPOFreeText: P6-PS is a 26-year-old male patient and was the only affected individual in a consanguineous family of Palestinian origin (Fig. 1d).

He presented the clinical features of RP, with vessel attenuation, RPE dystrophy without BSP, and CME in both eyes (Fig. 2d). He had a visual acuity of 0.5 D in both eyes, posterior subcapsular cataract and unrecordable ERG responses (Table 2). He also complained of mild-to-moderate hearing loss at low to mid frequencies (Fig. 3).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.170G>A (p.Trp57Ter).

ClinVar: N/A.

CAID: CA346167763.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case: 9237

CasePresentingHPOsFreeText: RP, A cohort of 266 patients with visual impairment diagnosed by different medical centers in the Netherlands were included in this study. The specific eye disorders were diagnosed by expert ophthalmologists based on appropriate clinical examinations.

CasePreviousTesting: WES

CaseGenotypingMethod: Sequencing of the exome was performed after the participants were counseled by a clinical geneticist at one of the medical university centers located in the Netherlands. DNA was extracted from peripheral blood using standard procedures. In all 266 cases, exome enrichment was performed using Agilent's SureSelect XT Human All Exon V4 (Agilent Technologies, Santa Clara, CA, USA). For 48 cases, next-generation sequencing was performed using a 5500xl SOLiD System (Life Technologies). All reported single-nucleotide variants have been validated by Sanger sequencing

Variant: c.2550_2553del, p.(Asp850fs)

ClinVarID: or CAID: CA658821678

gnomAD: absent

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: RFS169_Proband

CasePresentingHPOsFreeText: The prospectus was a 31-year-old Caucasian male whose major complaint was difficulty going down steps and curbs in dim light or at night. He was aware that his peripheral vision was poor and reported frequent inability to locate objects. His sister, mother, maternal aunt, maternal grandfather, maternal great-grandfather, and maternal great uncle had been diagnosed with RP (Figure 1B). He reported that his mother had severe night blindness at age 20 and was now 60 years old with extremely poor vision.

CasePreviousTesting: Each proband has been previously tested for mutations in the complete coding region of CA4, CRX, FSCN2, IMPDH1, NRL, PRPF31, RDS, RHO, ROM1, and RP9. Samples were also screened for mutations in mutational “hot spots” of RP1, PRPF3, PRPF8, and NR2E3.

CaseGenotypingMethod: PCR products were treated with ExoSapIt (USB, Cleveland, OH) and sequenced unidirectionally with BigDye v1.1 (Applied Biosystems) and the primers described in Table 1. PCR product sequencing was employed to screen patient DNA for mutations in the entire coding region and flanking intron/exon junction of TOPORS.

Variant: c.G2422T nonsense change, which resulted in a p.Glu808X in family.

ClinVarID: or CAID: CA373163668

gnomAD: absent

VariantEvidence: Analysis of this mutation in eight additional family members demonstrated that this mutation tracks with disease (Figure 1).

Case: MOL0369 Proband

CasePresentingHPOsFreeText: The ocular diagnosis was determined using a full ophthalmologic examination; full-field electroretinography; electro-oculography; color vision testing using the Panel D-15 test; optical coherence tomography; color, infrared, and fundus autofluorescence imaging; and fluorescein angiography, as detailed previously. The index case (patient II:1) received a diagnosis of RP at 20 years of age following complaints of impaired night vision and constricted visual fields. At 32 years of age, her electroretinographic responses were nondetectable (Table 1). At 49 years of age, her visual acuity (VA) was at the level of hand motions, and posterior polar cataract and posterior subcapsular opacity were evident. Fundus findings were compatible with advanced RP, including moderate pallor of the optic disc, widespread atrophy, and pigmentary changes. Optical coherence tomography revealed severe thinning of the outer nuclear layer and the epiretinal membranes. By 53 years of age, her VA decreased to the level of light perception with partial projection in both eyes. Her medical health record includes carcinoma of the cervix, which was diagnosed when she was 47 years of age and treated surgically with no sequela. She has mild hypertension, which is controlled by medication, and mild reflux. The results of a hearing test performed when she was 48 years of age were normal.

CasePreviousTesting: WES

CaseGenotypingMethod: we performed a series of mutation analyses, including APEX (arrayed primer extension)–based screening of all known RP mutations (http://www.asperbio.com/asper-ophthalmics) and screening for a set of mutations that we previously identified in patients with RP of the same origin (including mutations in the following genes: ABCA4, AIPL1, DHDDS, EYS, GUCY2D, NR2E3, RAB28, RPE65, and USH2A), Whole-exome sequencing evaluations for patients from 2 families (MOL0369

Variant: A subsequent analysis of other genes associated mainly with syndromic RP revealed the identification of 2 novel heterozygous missense variants in BBS2 (c.98C>A leading to p.A33D and c.401C>G leading to p.P134R) within the largest shared heterozygous region (Table 1). A segregation analysis showed that the mutations are in trans (ie, compound heterozygous mutations) and perfectly cosegregated with the disease

ClinVarID: or CAID: CA204968, CA204970

gnomAD: CA204968: allele frequency of 0.000002543 in the eurpoean non finnish population (v4.0.0); CA204970: allele frequency of 0.00002204 in the eurpoean non finnish population (v4.0.0)

AddCaseInfo:

FamilyName: MOL0369

Ethnicity: nonconsanguineous Moroccan Jewish family

Affected: 3

Unaffected:

Segregations:

eLOD:

AddSegregationInfo:

Case#: Patient 1, F, Age of Report: 32 y.o. Age of Onset: 28 y.o, Ethnicity: N/A.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030648 (Midperipheral), HP:0000543 (Optic disc pallor/waxy pallor of the optic disc), HP:0001133 (Constriction of peripheral visual field/constricted field with a remaining small central island)

CaseHPOFreeText: 32-year-old female presented four years ago with a unilateral decrease in vision in the left eye that she had had for a number of years. There was no family history of blindness or inherited eye diseases and her parents were first cousins.

She denied a previous history of ocular trauma, surgery and ocular inflammation. Her medical and drug history were unremarkable. The patient denied any neurological or hearing problems. She had best-corrected visual acuity (BCVA) of 20/20 and 20/40 in the right and left eye, respectively. Anterior segment examination of both eyes, as well as fundus examination of the right eye were unremarkable. Fundus examination of the left eye revealed midperipheral bone spicules, attenuated blood vessels and a waxy pallor of the optic disc (Figure 1).

Fundus autofluorescence revealed hypoautofluorescence corresponding to the bone spicules and hyperautofluorescence at the macular area with preserved foveal autofluorescence. SD-OCT of the right eye was unremarkable, while the left eye showed the loss of the parafoveal ellipsoid zone. The subfoveal ellipsoid zone was minimally affected. ffERG showed responses within normal limits in the right eye and non-recordable responses in the left eye (Figure 2). The Goldman visual field was normal in the right eye, while the left revealed a severely constricted field with a remaining small central island.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: NGS.

Variant: Variant 1: NM_021831.6:c.373C>T (p.Arg125Trp). Variant 2: NM_021831.6:c.730-22_730-19dup (n.730-22_730-19dup).

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

CAID: Variant 1: CA1567613. Variant 2: CA2586968849.

gnomAD: Variant 1: Frequency: 0.000007390. Link: https://gnomad.broadinstitute.org/variant/chr2-27053559-C-T?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis for parents and other family members was not possible. The patient had stable vision upon examination in both eyes during five years of follow-up visits with a stable average central macular thickness on SD-OCT (Table 2).

CasePMIDs: N/A.

Case: Patient 3

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. 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.208C>T (p.Arg70Trp)

ClinVarID: or CAID: CA412927449

gnomAD: not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Lin_FamilyC_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: Genetic testing was performed in all four patients in this study, using either or targeted capture sequencing of 280 retinal dystrophy-related genes (C-II:1).

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either or targeted capture sequencing of 280 retinal dystrophy-related genes (C-II:1).

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

ClinVarID: or CAID: CA151548

gnomAD: allele frequency of 0.001173 in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case#: 46-year-old, M, Age of report: 46 y.o., Ethnicity: Han Chinese.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0001696 (Situs inversus totalis), HP:0003251 (Male infertility), HP:0000662 (Nyctalopia/Night blindness), HP:0012207 (Reduced Sperm Motility), HP:0011109 (Chronic sinusitis), HP:0000458 (Anosmia/Permanently impaired olfactory sensation), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous family.

The proband complained of pronounced vision decline over the last 2 years. He had experienced night blindness over the last decade and was diagnosed with RP at age 33. His best-corrected visual acuity (BCVA) was 0.6 in both eyes, with −3.75-0.75 × 85 OD and − 3.25-1.25 × 65 OS.

Dilated fundus examination revealed sparse bone spicule pigment deposits, widespread mottled pigmentation in the mid-peripheral retina, and attenuated retinal vessels (Figure 1A). Fundus autofluorescence imaging exhibited hypofluorescence outside the vascular arcades and a characteristic hyperfluorescent ring around the fovea (Figure 1B). Optical coherence tomography (OCT) images showed a retained central island within the outer nuclear layer and ellipsoid zone (Figure 1C). Electroretinography indicated extinguished responses.

Four-year follow-up data combined with past medical history revealed slow vision degeneration. BCVA in both eyes was 0.1 at age 41, 0.8 at age 44, and 0.5 at age 50. Fundoscopy demonstrated larger, more peripheral retinal pigment epithelium atrophy with age, corresponding to hypofluorescent patches in fundus autofluorescence (Figure 1B). OCT images demonstrated ellipsoid zone peripheral loss, which progressed to the central fovea over time (Figure 1C). The severe peripheral visual field constriction observed in his forties worsened considerably with age. At age 50, all peripheral visual fields outside the central 5° were bilaterally lost (Figure 1D).

A review of his medical history during the second visit revealed full thoracic and abdominal situs inversus (Figure 1E). Routine semen analysis found that sperm motility was severely reduced, resulting in infertility (Table 1). Furthermore, this patient had chronic sinusitis, and olfactory sensation was permanently impaired following a severe cold at age of 49.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Next-generation sequencing. Sanger sequencing and segregation analysis indicated his siblings carried the same heterozygous variant (Figure 2A, B).

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole exome sequencing (WES) for proband and his siblings

Variant: NM_012106.4:c.22_23del.

ClinVar: N/A.

CAID: CA495624174.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: GC17880, Presumed F, Age of Report: 37 y.o. Ethnicity: N/A.

CasePresentingHPOs: HP:0030786 (Photopsia), HP:0000662 (Nyctalopia), HP:0001123 (Visual field defect/field defects), HP:0000585 (Band keratopathy/Left band keratopathy), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband was diagnosed with simplex RP and was the second of three siblings born to first-cousin parents with no family history of eye disease, underwent WES revealing 21,404 coding variants.

Other reported symptoms include: Irregular pigmented lesions in periphery, foveal/parafoveal cysts.

Fields to confrontation age 36 years less than 30 degrees.

Proband also was diagnosed with left band keratopathy, Wolf-Parkinson White syndrome, 4 miscarriages.

CaseNotHPOs: HP:0005268 (Miscarriage), HP:0001716 (Wolff-Parkinson-White syndrome)

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_001130955.1:c.1617+5G>A.

ClinVar ID: 417758.

gnomAD: Frequency: 0.000003099. Link: https://gnomad.broadinstitute.org/variant/19-7456408-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: CA16616865.

CasePMIDs: N/A.

Case#: GC3626, M, Age of Report: 51 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0030786 (Photopsia), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000543 (Optic disc pallor/pale discs), HP:0011505 (Cystoid macular edema), HP:0031527 (Retinal edema), HP:0011531 (Vitritis/Vitritis cells), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, following a previous diagnosis of Stargardt's macular dystrophy almost 1 decade earlier. First onset of night vision loss was reportedly in his teens.

Other reported symptoms include: Irregular pigmented lesions in periphery, pale discs, cystoid macular edema, peripheral telangiectasia with some retinal edema and vitreous cells, possible para-arteriolar sparing.

Goldmann visual fields age 29: ring scotoma at 30 degrees, binocular Esterman age 36: central 20 degrees only retained.

Also diagnosed with L Fuch’s heterochromic cyclitis.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_001367823.1:c.3196G>T. Variant 2: NM_001367823.1:c.3302_3325del.

ClinVar ID: Variant 1: 417757. Variant 2: 417756.

gnomAD: Variant 1: Frequency: 6.524e-7 (Allele Frequency). Link: https://gnomad.broadinstitute.org/variant/19-7467400-G-T?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: Variant 1: CA16616864. Variant 2: CA16616863.

CasePMIDs: N/A.

Case#: GC18203, F, Age of Diagnosis: 37 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000543 (Optic disc pallor/pale discs), HP:0011505 (Cystoid macular edema), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: The proband was diagnosed with simplex retinitis pigmentosa. The proband is the second of two siblings born to unrelated parents with no family history of eye disease.

At 20 yrs of age, the proband developed the following symptoms: reduced acuity, mild nyctalopia and blind spots.

Other reported symptoms include irregular peripheral pigment, pale discs, cystoid macular edema, vitreous opacities, attenuated sheathed vessels, peripheral retinal exudate.

Octopus visual fields age 36 central 20-30 degrees retained on R , 30-50 degrees on L, age 37 24-2 central scotomas, fields now constricted to 15 degrees each eye.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Sanger sequencing of CRB1.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_001367823.1:c.808A>G. Variant 2: NM_001367823.1:c.2560C>T.

ClinVar ID: Variant 1: N/A. Variant 2: 417755.

gnomAD: Variant 1: Frequency: 0. Link:https://gnomad.broadinstitute.org/variant/19-7382877-A-G?dataset=gnomad_r4. Variant 2: Frequency: 0.000002920. Link: https://gnomad.broadinstitute.org/variant/19-7462259-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Variant 1: CA403164517. Variant 2: CA16616862.

CasePMIDs: N/A

Case: German

CasePresentingHPOsFreeText: We report mutations in the gene for topoisomerase I–binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP)

CasePreviousTesting: Sequencing of the coding regions of all other genes in the RP31 critical region revealed only nonpathogenic sequence variants.

CaseGenotypingMethod:

Variant: a 2-bp deletion (c.2552_2553delGA) in exon 3 leading to p.Arg851fs

ClinVarID: or CAID: CA645509428

gnomAD: absent

VariantEvidence: c.2556_2557del p.Glu852AspfsTer20, check for NMD

Case: French Canadian

CasePresentingHPOsFreeText: We report mutations in the gene for topoisomerase I–binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP)

CasePreviousTesting: Sequencing of the coding regions of all other genes in the RP31 critical region revealed only nonpathogenic sequence variants.

CaseGenotypingMethod:

Variant: heterozygous 1-bp insertion (c.2474_2475insA) in exon 3; this frameshift mutation segregates with the affected status and is predicted to result in a premature stop codon (p.Tyr825fs)

ClinVarID: or CAID: CA913185045

gnomAD: absent

VariantEvidence: NM_005802.5:c.2474dup (p.Tyr825Ter), check for NMD. LOD score for segregation of variant in this family is reported in PMID: 16189705

Case#: 42-year-old woman, F, Age of Report: 42 y.o., Ethnicity: Palestinian descent.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field/worsened peripheral vision), HP:0000523 (Subcapsular cataract), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Proband was consanguineous - A multi-generational pedigree indicated her parents were first cousins of Palestinian descent.

A 42-year-old woman was referred for possible retinitis pigmentosa (RP). She had increasing nyctalopia since age 26. Recently, she had noticed worsened peripheral vision. She was taking ziprasidone for schizophrenia. She was otherwise well.

On examination, best corrected visual acuity was hand motion right eye and 20/50 left eye. Cycloplegic refraction was −4.00 + 1.00 × 90 OD, −3.00 + 1.00 × 90 OS. Pupillary responses and eye movements were normal. She did intermittently eccentrically fixate with the left eye. Slit lamp examination was normal with the exception of bilateral, dense, superior posterior subcapsular cataract, which did not involve the visual axis. Goldmann applanation tonometry was normal. Fundus examination showed moderate optic atrophy, moderate retinal vessel attenuation, almost 360 degrees of “bone spicule” pigmentary clumping, attenuation of the retinal vessels, and bilateral preserved central foveal islands of normal retina (Figure 4a). No optic nerve drusen were seen in the fundus examination. OCT showed an almost complete loss of photoreceptors, except for the subperifovea in both eyes (Figure 4b). FAF of the right eye was of poor quality. FAF of the left eye had marked peripapillary hypofluorescence (Figure 4c). She had maculopathy in the left eye with a central hyperautofluorescent ring inside of an area of mottled hypoautofluorescence. Visual fields were constricted to less than 10 degrees in each eye. Full field and multifocal ERG were isoelectric.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Inherited Retinal Dystrophies Sequencing Panel.

Variant: NM_021831.6:c.658C>T (p.Arg220Ter).

ClinVar: 2869501.

CAID: CA346173755.

gnomAD: N/A..

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis revealed that the unaffected mother and father were heterozygous for AGBL5: c.658C>T (p.Arg220*).

CasePMIDs: N/A.

Case#: Patient 13, female, Han origin, 1.5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Hernia, Airway obstruction (HP:0100790, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.1 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: CA55961718

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

Variant2ClinVarID: 556358

Variant2CAID: CA55961718

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 by parental testing.

PreviouslyPublished N/A

Case#: Patient 28, male, Han origin, 1 year 9 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 1.1 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.710T>G (p.L237R)

Variant1ClinVarID: N/A

Variant1CAID: CA355962113

Variant2: c.973-4G>A

Variant2ClinVarID: 558027

Variant2CAID: CA2802154

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

This paper was listed under the ClinVar entry for this variant; however, only as an example to prove loss-of-function variants in IDUA are known to be pathogenic

Case#: Patient 6, male, Han origin, 13 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly (HP:0000256)

CaseHPOFreeText: Cardiac disease

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

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.589G>A (p.G197S)

Variant2ClinVarID: 1526094

Variant2CAID: CA355961839

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 16, male, Han origin, 2.5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

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: N/A

CaseNotHPOs: N/A

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.2T>C (p.M1?)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

Variant2: c.1593delG (p.Leu532CysfsTer28)

Variant2ClinVarID: N/A

Variant2CAID: CA2586965986

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 23, male, Han origin, 3.5 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: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 3.5 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.1-2C>G

Variant1ClinVarID: N/A

Variant1CAID: CA2586973510

Variant2: c.1189+5G>T

Variant2ClinVarID: N/A

Variant2CAID: CA2586965966

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 2, Han origin, male, 1 year and 3 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Airway obstruction (HP:0006536)

CaseNotHPOFreeText: N/A

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.159C>A (p.C53X)

Variant1ClinVarID: 1458768

Variant1CAID: CA355945972

Variant2: c.546G>C (p.E182D)

Variant2ClinVarID: 4069690

Variant2CAID: CA355961740

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 29, male, Han origin, 11 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

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

CaseNotHPOFreeText: N/A

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.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

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 35, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Mongolian macula (HP:0011369)

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.1227dupG (paper says c.1225dupC but according to the variant sequence this should be c.1227dupG - a known variant)

Variant1ClinVarID: 929237

Variant1CAID: CA1139658406

Variant2: c.1244_1271del27 - Allele registry states that the range is off by 1, noting a deletion of 28 being found instead of 27.

Variant2ClinVarID: N/A

Variant2CAID: N/A

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

article is a PDF, so annotating here.

Case#: Beesley Family 30, UK

DiseaseAssertion: MPS1, Scheie

FamilyInfo: Family 30, no parental material available to confirm phase

CasePresentingHPOs:

CaseHPOFreeText: reduced/absent enzyme activity. IDUA enzyme activity in leukocytes= range from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) for the 85 patients in study, but no individual activity provided. No individual phenotype information given. Scheie described as milder with "aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation."

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: intron/exon boundaries of the IDUA gene were analysed by PCR, SSCP and DNA sequencing

PreviouslyPublished: n/a

Variant: compound het: 678–7g>a; Q400X

ClinVar: 1683229

CAID: CA355963534

SupplementalData: n/a

Case#: Family 7, UK

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1650+5G>A; IVS12+5G>A in the paper

Variant2ClinVarID: 92634

Variant2CAID: CA220504

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 25, UK

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 30, UK

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The Scheie phenotype is characterized by aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation. This is a general assessment and not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.590-7G>A; c.678-7G>A in the paper (old nomenclature)

Variant1ClinVarID: 222996

Variant1CAID: CA356990

Variant2: c.1198C>T (p.Q400X)

Variant2ClinVarID: 1683229

Variant2CAID: CA355963534

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 17, Cyprus

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.659delG; c.747delG in the paper (old nomenclature)

Variant1ClinVarID: N/A

Variant1CAID: CA2802045

Variant2: c.659delG; c.747delG in the paper (old nomenclature)

Variant2ClinVarID: N/A

Variant2CAID: CA2802045

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 20, UK

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.65delC; c.153delC in the paper (old nomenclature)

Variant2ClinVarID: 929238

Variant2CAID: CA437911597

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5 (see Table 2), 37 weeks, 5 days (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.26 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.46_57del (p.Ser16_Ala19del) (c.134del12)

Variant2ClinVarID: 92643

Variant2CAID: CA220509

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished c.134del12 is based on old numbering. The variant is referred to as "134del12" in older papers. The correct name is: NM_000203.5(IDUA):c.46_57del (p.Ser16_Ala19del)

Case#: Patient 1 (see Table 2), 37 weeks (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Inguinal hernia (HP:0000023)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 0.31 nmol x mg-1 × hr-1

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)

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 27 (see Table 2), Gestational age unavailable

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 1.70 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA:234128

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

Variant2ClinVarID: 558189

Variant2CAID: CA:2802205

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12 (see Table 2), 40 weeks (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.653T>C (p.L218P)

Variant1ClinVarID: 222995

Variant1CAID: CA:356986

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

Variant2ClinVarID: 222995

Variant2CAID: CA:356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8, Turkish

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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, Turkish

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.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 7, Turkish

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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 21, born in 2000 (paper published in 2017), 22 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: 48 ng/mol (36 weight matched enzyme reference assay)

CaseUrineGAGs: 0.63 DS/CS

CaseERT: No

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.64_65delC (p.Pro22GlyfsTer?)

Variant2ClinVarID: N/A

Variant2CAID: CA3246685724

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 17, born in 2009 (paper published in 2017), 1 year (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: 48 ng/mol (38 weight matched enzyme reference assay)

CaseUrineGAGs: 0.42 DS/CS

CaseERT: Yes

CaseBMT: Yes, MUD

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 4, born in 1996 (paper published in 2017), 10 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding, retinopathy (HP:0007957, HP:0000488)

CaseHPOFreeText: N/A

CaseNotHPOs: Cataract (HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 32.77 ng/mol (46.19 weight matched enzyme reference assay)

CaseUrineGAGs: 1.08 DS/CS

CaseERT: No

CaseBMT: Yes, Sib

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 25, born in 2005 (paper published in 2017), 20 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: 43 ng/mol (28 weight matched enzyme reference assay)

CaseUrineGAGs: 0.45 DS/CS

CaseERT: Yes

CaseBMT: Yes, Cord

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.386-1G>A

Variant2ClinVarID: 1458772

Variant2CAID: CA355961254

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 18, born in 2012 (paper published in 2017), 7 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: 79.39 ng/mol (42.66 weight matched enzyme reference assay)

CaseUrineGAGs: 0.51 DS/CS

CaseERT: Yes

CaseBMT: Yes, Uncle

Variant1: c.1045G>T (p.D349Y)

Variant1ClinVarID: 638075

Variant1CAID: CA355963146

Variant2: c.1045G>T (p.D349Y)

Variant2ClinVarID: 638075

Variant2CAID: CA355963146

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 20, born in 2003 (paper published in 2017), 20 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: 57.2 ng/mol (26 weight matched enzyme reference assay)

CaseUrineGAGs: 0.63 DS/CS

CaseERT: No

CaseBMT: Yes, Cord

Variant1: c.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1898C>A (p.S633X)

Variant2ClinVarID: 1068474

Variant2CAID: CA355966009

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 95, Turkey

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.1306G>C (p.A436P)

Variant1ClinVarID: N/A

Variant1CAID: CA355963897

Variant2: c.1306G>C (p.A436P)

Variant2ClinVarID: N/A

Variant2CAID: CA355963897

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 51, Poland

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.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: Nomenclature in the paper - c.1398delC; current nomenclature - c.1400del p.Pro467ArgfsTer?)

Variant2ClinVarID: 3910474

Variant2CAID: CA2586965982

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 6, 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.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 14, 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.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: c.1333_1335del (p.Asp445del)

Variant2ClinVarID: 840115

Variant2CAID: CA916082626

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 89, 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.826_828del (p.Glu276del)

Variant1ClinVarID: 2734638

Variant1CAID: CA2586965949

Variant2: c.826_828del (p.Glu276del)

Variant2ClinVarID: 2734638

Variant2CAID: CA2586965949

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, 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.1487C>G (p.P496R)

Variant1ClinVarID: 496861

Variant1CAID: CA2802275

Variant2: c.793G>C (p.G265R)

Variant2ClinVarID: 638074

Variant2CAID: CA2802098

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 11, 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.532G>A (p.E178K)

Variant2ClinVarID: 2203495

Variant2CAID: CA355961709

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 30, 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.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 79, Turkey

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1727+6T>A

Variant1ClinVarID: 2203499

Variant1CAID: CA2580070698

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 13, 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.265C>T (p.R89W)

Variant1ClinVarID: 580286

Variant1CAID: CA2801156

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 19, 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.1727+1G>A

Variant1ClinVarID: 638077

Variant1CAID: CA355965296

Variant2: c.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 33, 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.1487C>G (p.P496R)

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: P5, Male, 3.1 years (diagnosed), 4.2 (report), 17 kg (weight), 93 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

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

CasePresentingHPOs: HP:0001999, HP:0002240, HP:0100790, HP:0007957 (Facial Dysmorphic Features, Hepatomegaly, Hernia(Ombelical), Corneal Opacity)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency)

CaseNotHPOs: HP:0001249, HP:0001387, (Mental Retardation, Joint Stiffness)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA Enzyme activity 15 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 11 (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#: P1, Male, 5.5 years (diagnosed), 13.8 (report), 28 kg (weight), 132 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0001999, HP:0000943, HP:0001387, HP:0002240, HP:0100790, HP:0000365, HP:0000238 (Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatomegaly, Hernia(Ombelical), Deafness(bilateral transmission), Hydrocephalus)

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency)

CaseNotHPOs: HP:0001249, HP:0007957 (Mental Retardation, Corneal Opacity)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 7 (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#: P3, Female, 15.7 years (diagnosed), 22.6 (report), 27 kg (weight), 128 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0001999, HP:0000943, HP:0002240, HP:0001387, HP:0007957, HP:0000238 (Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia(Ombelical), Corneal Opacity, Hydrocephalus)

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

CaseNotHPOs: HP:0001249, (Mental Retardation)

CaseNotHPOFreeText: HM/HSM

CaseEnzymeAssay: IDUA Enzyme activity 6 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 95 (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#: P9, Female, 8.3 years (diagnosed), 14.9 (report), 35 kg (weight), 135 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001999, HP:0000943, HP:0001433, HP:0100790, HP:0000365, HP:0000238 (Facial Dysmorphic Features, Multiple Dysostosis, Hepatosplenomegaly, Hernia(Ombelical), Deafness(mixed), Hydrocephalus)

CaseHPOFreeText: Cardiac Manifestations(Mitral Insufficiency & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, HP:0001387, HP:0007957 (Mental Retardation, Joint Stiffness, Corneal Opacity)

CaseNotHPOFreeText: Chronic Rhinorrhea

CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 23 (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#: Patient No. 8, Persian ethnic group, female, 1.97 years old (age at time of gene therapy),

DiseaseAssertion: MPS-IH

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Yes

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

Variant1ClinVarID: N/A

Variant1CAID: CA355962006

Variant2: c.1104_1105delCT (p.F369PfsX29)

Variant2ClinVarID: N/A

Variant2CAID: CA2586965957

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient No. 6 (Table 1), White race, male, 2.13 years old (age at time of gene therapy), 85 IQ score, 1.96 years since gene therapy (1.5 years since latest visit)

DiseaseAssertion: MPS-IH

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Yes

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

Variant1ClinVarID: 11908