Case#: Schiaffino_1995_Family_2948_Patient_BA442, male, age not reported, family origin reported as British in two previous publications

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646).

CaseMethod1: Linkage mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646), and the proband was genotyped in this study by Sanger sequencing of PCR products from the 9 exons of GPR143.

Variant: The proband harbors the NM_000273.3(GPR143):c.216_232del (p.Ala73fs) variant in the hemizygous state.

ClinVar: 98619

gnomAD: This variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_000273.3(GPR143):c.216_232del (p.Ala73fs) is a frameshift variant in exon 1 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 82% of the protein product.

CaseAddInfo: The variant observed in this proband has been previously reported in two other studies (PMID: 1355560, PMID: 8301646).

CasePMIDs: PMID: 1355560, PMID: 8301646

Case#: Collin_2008_Family_A_Patient_II-1, male, 61 years of age at time of study, 12 years of age at onset, family ethnicity likely to be of Dutch origin based on the description of the majority of the cohort as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, Bone spicule pigmentation of the retina HP:0007737, Attenuation of retinal blood vessels HP:0007843, Constriction of peripheral visual field HP:0001133, Undetectable electroretinogram HP:0000550, Posterior subcapsular cataract HP:0007787, Optic disc pallor HP:0000543, Peripheral retinal atrophy HP:0200070, Reduced visual acuity HP:0007663

CaseHPOFreeText: The patient has been diagnosed with retinitis pigmentosa and has been described as displaying abnormalities characteristic of this diagnosis. Night blindness was the initial symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Because of the autosomal recessive pattern of inheritance in the patient's family, he and his family members were subjected to homozygosity mapping, identifying a homozygous region on chromosome 6 shared by affected members.

CaseMethod1: Homozygosity mapping within the family

CaseMethod2: Sanger sequencing of 44 PCR-amplified exons from the EYS locus

CaseGenotypingMethod: The proband was genotyped by homozygosity mapping of family members, followed by Sanger sequencing of 44 PCR-amplified exons from the EYS locus.

Variant: The proband harbors the NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) variant in the homozygous state.

ClinVar: 538

gnomAD: NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) is found in gnomAD v2.1.1 at a frequency of 0.00004991 (1/20038) in the Latino / Admixed American population https://gnomad.broadinstitute.org/variant/6-64430522-A-T

VariantEvidence: NM_001142800.2(EYS):c.9405T>A (p.Tyr3135Ter) is a nonsense variant in exon 44 of 44 that is not predicted to trigger nonsense-mediated decay but rather to disrupt the C-terminal 1% of the protein product.

CaseAddInfo: The proband is a member of Family A and has a similarly affected sister sharing the same genotype, as well as four unaffected siblings who are either heterozygous carriers or non-carriers of the variant.

CasePMIDs: N/A

Case#: Bandah-Rozenfeld_2010_NAP1_proband, female, age 30 years at time of diagnosis, in the 6th decade of life at the time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0032122 (Very low visual acuity), HP:0000577 (Exotropia), HP:0000639 (Nystagmus), HP:0007787 (Posterior subcapsular cataract), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The patient has been diagnosed with advanced retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant in the homozygous state.

ClinVar: 3549

gnomAD: The NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006152 (1/16256, with 0 homozygotes) in the African / African-American population. https://gnomad.broadinstitute.org/variant/3-100961664-G-A

VariantEvidence: NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) is a nonsense variant in exon 14 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 22% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being second cousins.

CasePMIDs: N/A

Case#: JU1426 (Family 10, II:3), Japanese male, 59 years (report)

CaseHPOsFreeText: Best-corrected visual acuity of zero in both eyes; fundus exam - inconspicuous, partial white dots at peripheral retina, and macular degeneration in both eyes; reduced fundus autofluorescence, and irregular autofluorescence around fovea in both eyes; Optical coherence tomography - diffuse disruption of ellipsoid zone and interdigitation zone with foveal sparing in both eyes; 30 min dark adapted ERG showed extinguished b-waves, and with dark adaptation of 2-3 hours there was partial recovery of b-waves.

CaseGenotypingMethod: WES

Variant: NM_002905.4:c.259C>T (p.Gln87Ter) homozygous

ClinVar: N/A

CAID: CA385200238

gnomAD: Not in gnomAD

CaseAddInfo: Estimated age (based on years of follow up)

Score: 2 points. This individual, with a diagnosis of fundus albipunctatus is homozygous for a nonsense variant in RDH5. This variant is absent in gnomAD.

Case#: Ayyagari_2002_Family_UM:F1088_Patient_III-16, male, 48 years old, ethnicity not descibed

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0007722 (Retinal pigment epithelial atrophy), HP:0003596 (Middle age onset), HP:0031624 (Moderate myopia), HP:0000603 (Central scotoma)

CaseHPOFreeText: Onset of symptoms was approximately at age 43. The proband has been diagnosed with atrophic macular degeneration, with the family exhibiting X-linked pattern of inheritance.

CaseNotHPOs: HP:0000580 (Pigmentary retinopathy), HP:0030491 (Choriocapillaris atrophy), HP:0008046 (Abnormal retinal vascular morphology), HP:0000512 (Abnormal electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to linkage analysis using microsatellite markers along the length of the X chromosome (LOD score of 4.17 associated with marker DXS1058.

CaseMethod1: Sanger sequencing of the PCR-amplified exons from the NYX locus

CaseMethod2: Sanger sequencing of the PCR-amplified exons from the RPGR locus

CaseGenotypingMethod: The proband and his family members were subjected to linkage analysis using microsatellite markers along the length of the X chromosome, followed by Sanger sequencing of the PCR-amplified exons from the NYX and RPGR loci.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2917G>T (p.Glu973Ter) variant in the hemizygous state.

ClinVar: 866129

gnomAD: The variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.2917G>T (p.Glu973Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay but truncates ~16% of the C-terminus of the protein product.

CaseAddInfo: The proband is a member of Family UM:F1088, shown in Figure 1 from this study. Ten other genotype-positive affected males are present in his extended family, as well as carrier females affected with mild perimacular RPE depigmentation and tapetal reflex.

CasePMIDs: N/A

Case#: Kelsell_1998_CORD6_Family_Proband, male, age 48 at time of report, nationality listed as British

CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseHPOFreeText: The text asserts that In all members of the proband's family, central vision was lost before age 7, while peripheral field vision was lost by the fourth decade of life. Cone ERG was undetectable early on in the disease, while rod ERG abnormalities later developed progressively.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: In a previous publication (PMID: 9097965), the family was subjected to (genome-wide) linkage analysis mapping the affected phenotype to chromosome 17p12-p13. The LOD score associated with marker locus D17S1844 was 5.93 (with no recombination).

CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and his family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.3(GUCY2D):c.[2511G>C;2512C>A] variant in the heterozygous state.

ClinVar: 453243

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.3(GUCY2D):c.[2511G>C;2512C>A] is a missense variant that causes two adjacent substitutions at the protein level (p.Glu837Asp;Arg838Ser), located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Ser substitution has also been shown to disrupt the calcium-dependent regulation of GUCY2D by GUCA1A (PMID: 15504042), decrease sensitivity to inhibition by RD3 (PMID: 27703005), and trigger blindness in a transgenic mouse model (PMID: 27703005).

CaseAddInfo: The family's variant was not comprehensively genotyped in this publication but was later identified in PMID: 10647719.

CasePMIDs: PMID: 9097965, PMID: 10647719, PMID: 11565546

Case#: Family_11864_Proband_II-2, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: High myopia HP:0011003, Blurred vision HP:0000622, Childhood onset HP:0011463, Protanopia HP:0011522

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of early onset high myopia, with onset in early childhood and either high myopia or axial length >25 mm before age 7, or refractive errors <-10 as an adult.

CaseNotHPOs: Nystagmus HP:0000639, Photophobia HP:0000613, Nyctalopia HP:0000662

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing.

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by either targeted exome sequencing or whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.427_433dup (p.Ala145ValfsTer23) variant in the hemizygous state.

CAID: CA2695237718

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6(OPN1LW):c.427_433dup (p.Ala145ValfsTer23) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. The variant was inherited from the proband's unaffected mother.

CasePMIDs: N/A

Case#: Delvallée_2021_Proband_D.II-2, female, age not described, family origin reported as from Denmark and Sweden, ancestry reported as European

CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0001162 (Postaxial hand polydactyly), HP:0030084 (Clinodactyly), HP:0001513 (Obesity), HP:0000119 (Abnormality of the genitourinary system)

CaseHPOFreeText: The proband additionally exhibits slow ideation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.

CaseMethod1: targeted exome sequencing

CaseMethod2: Sanger sequencing of BBS1

CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.

ClinVar ID: 12143, 981241

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.

CaseAddInfo: The proband's family indicates segregation of the two variants from the two heterozygous unaffected carrier parents.

CasePMIDs: N/A

Case#: Thiadens_2009_Family_A_Proband_AII-2, male, age 6 years at onset and 51 years at the time of report, sites of treatment listed as the Netherlands, Belgium, U.K., or Canada

CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as severe), HP:0030825 (Absent foveal reflex), HP:0007703 (Abnormality of retinal pigmentation, described as mild), HP:0030465 (Undetectable light-adapted electroretinogram)

CaseHPOFreeText: The proband and affected family member were previously diagnosed with early onset autosomal recessive cone dystrophy. The proband had onset by age 6 years.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family.

CaseMethod1: homozygosity mapping

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: Affected and unaffected family members were initially subjected to homozygosity mapping based on Affymetrix GeneChIP SNP analysis, identifying an 11-Mb region of homozygosity shared with another unrelated family. The clear candidate gene, PDE6C, was then subjected to Sanger sequencing-based screening of the 22 exons and flanking regions.

Variant: The proband harbors the NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant in the homozygous state.

ClinVar ID: 8763

gnomAD: The NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) variant is found in gnomAD v2.1.1 at a frequency of 0.00008009 (2/24972) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95372567-C-T

VariantEvidence: NM_006204.4(PDE6C):c.85C>T (p.Arg29Trp) is a missense variant that does not have experimental evidence of a functional effect on the protein product. However, it has been reported in similarly affected individuals in other studies (PMID: 21127010, PMID: 30080950).

CaseAddInfo: The patient's affected sibling shares the same homozygous genotype, while the parents are unaffected and unrelated at least during the last 3 generations.

CasePMIDs: N/A

Case#: Weigell-Weber_2000_adCRD_Family_Proband, age and gender not specified, nationality listed as Swiss

CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0000512 (Abnormal electroretinogram), HP:0000529 (Progressive visual loss), HP:0001123 (Visual field defect), HP:0000613 (Photophobia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and family members were subjected to linkage analysis excluding linkage to candidate loci at chr19q13, chr6q13-q15, and chr6p21, and confirming linkage to chr17p (using the microsatellite

CaseMethod1: Sanger sequencing of PCR products from each of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and his family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) variant in the heterozygous state.

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838His substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Sergouniotis_2011_Proband_A-2, female, age 34 years, family ethnic origin described as Middle Eastern

CasePresentingHPOs: Congenital nystagmus HP:0006934, Presenile cataracts HP:0007819, Reduced visual acuity HP:0007663, Nyctalopia HP:0000662, Constriction of peripheral visual field HP:00011

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis shortly after birth. Fundoscopy results were described as "significant pigment at the level of the retinal pigment epithelium and in a configuration unlike that of typical RP".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by a combination of homozygosity mapping and exome sequencing.

CaseMethod1: homozygosity mapping and exome sequencing

CaseMethod2: Sanger sequencing of the proband and family members to confirm the presence of the variant and to test segregation

CaseGenotypingMethod: The proband was initially genotyped by a combination of homozygosity mapping and exome sequencing. Sanger sequencing of the proband and family members was then performed to confirm the presence of the variant and to test segregation.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter) variant.

ClinVar: 30331

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_002242.4(KCNJ13):c.496C>T (p.Arg166Ter) is a nonsense variant in exon 3 of 3 that is not predicted to trigger nonsense-mediated decay but rather to truncate the C-terminal 54% of the protein product.

CaseAddInfo: The proband's family history includes consanguinity and a sibling similarly diagnosed with LCA.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FVII1, male, 18 months of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0011968 (Feeding difficulties), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010306 (Short thorax), HP:0000773 (Short ribs), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000093 (Proteinuria), HP:0001970 (Tubulointerstitial nephritis), HP:0004719 (Hyperechogenic kidneys)

CaseHPOFreeText: This proband was diagnosed with Jeune syndrome, unlike the other probands in this study who were diagnosed with Mainzer-Saldino syndrome. Limbs are described as trident. Elevated urea listed as a kidney-related phenotype.

CaseNotHPOs: HP:0025404 (Abnormal visual fixation), HP:0004322 (Short stature), HP:0000929 (Abnormal skull morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2399+1G>T variants in IFT140.

ClinVar: 31683, 31680

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.2399+1G>T variant is present in gnomAD at a frequency of 0.0001231 in the European (non-Finnish) population (14/113764, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607935-C-A

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). The NM_014714.4(IFT140):c.2399+1G>T variant disrupts a canonical splice donor site and is predicted but not confirmed to trigger skipping of exon 18/31.

CaseAddInfo: The proband's parents are reportedly non-consanguineous.

CasePMIDs: N/A

Case#: Li_2015_Proband_HM429III3, onset before age 7 years, male, seen at a medical center in Guangzhou

CasePresentingHPOs: Abnormal optic disc morphology HP:0012795, Abnormal morphology of the choroidal vasculature HP:0025568, Abnormal light-adapted electroretinogram HP:0008275, Protanopia HP:0011522

CaseHPOFreeText: The proband has a diagnosis of early onset high myopia, yet also shows protanopia. He exhibits myopic fundus changes, with temporal crescent of optic nerve head and tigroid appearance of posterior retina. Rod ERG responses are normal, while cone responses are mildly to moderately reduced.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by whole exome sequencing.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

CaseGenotypingMethod: Genotyping of the proband was performed by whole exome sequencing, followed by Sanger sequencing of OPN1LW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.617_620dup (p.Phe208ArgfsTer51) variant in the hemizygous state.

CAID: CA2739290587

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_020061.6(OPN1LW):c.617_620dup (p.Phe208ArgfsTer51) is a nonsense variant in exon 4 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. 4 other male family members are similarly affected but ungenotyped.

CasePMIDs: N/A

Case#: Holmberg_Patient_1, male, age 3 at onset and age 15 at time of study, Finnish origin

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)

CaseHPOFreeText: Age of onset was 3, while mental decline was present at age 3 and both visual deterioration and abolished ERG at age 6. The patient had progressive cerebral atrophy starting between the ages of 6 and 7. Ataxia and seizures were found at age 8. Loss of independent walking occurred at age 9. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Giant flash visual evoked potentials were found at age 10.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case: Saihan_2009_Family_patient_III:4, male, British (of Welsh origin), 47 years old at presentation

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The mother of the proband and affected siblings was unaffected and negative for the variant, while the father was affected but not genotyped.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0031239 (Extrafoveal choroidal neovascularization), HP:0031528 (Subretinal deposits),

CaseHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 year prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 47). Vision loss in one eye occurred suddenly at age 48, but had not occurred in the other eye by age 51. Occasional drusen-like deposits were present at the posterior pole. Choroidal neovascularization was hemorrhagic and initiated loss of central vision. A large tear was observed in the retinal pigment epithelium. RPE-choroid complex showed increased reflectivity in both eyes. Left eye had signs of retinal atrophy.

CaseNotHPOs: HP:0004328 (Abnormal anterior eye segment morphology), HP:0000518 (Cataract)

CaseNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members. Left eye was largely unaffected at the time of evaluation.

CasePreviousTesting: Family history (indicating autosomal dominant inheritance of retinal degeneration) and ophthalmic exams (including LogMAR visual acuities, slit-lamp biomicroscopy, color fundus photography, optical coherence tomography scans of the fovea, and autofluorescent imaging of the fundus).

GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: The Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

VariantEvidence: When the missense variant was exogenously expressed in a retinal epithelial cell line, reverse zymographs of the extracellular matrix revealed the presence of both monomeric and dimeric species for the variant but only the monomeric species for the wild-type. This indicated that the free cysteine present in the variant did not compromise metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of inheritance.

Case: Langton_2000_Family_1_patient_II2, female, country of origin northeast England (PMID:11734514), onset at 25 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Variant inherited by the proband rather than acquired de novo, although parents were not genotyped.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0032284 (Ultra-low vision with retained motion projection), HP:0000533 (Chorioretinal atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: Presentation at age 25 was with nyctalopia and loss of central vision. At age of 72, remaining visual acuity was limited to retained motion projection, and chorioretinal atrophy was complete in each macula. Pigmentation was observed in the retinal periphery.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Rheumatological exam and renal function were both normal.

CasePreviousTesting: Phenotypic characterization only

GenotypingMethod: PCR of TIMP3 exon 5 followed by Sanger sequencing of the PCR product

PreviouslyPublished: PMID:11734514

SupplementalData: N/A

Variant: The NM_000362.5(TIMP3):c.484G>T, p.Glu139X variant converts the GAG codon to a TAG, resulting in early termination of the transcript. This nonsense substitution affects the final exon 5, so that truncation of the protein product is predicted but not nonsense-mediated decay of the transcript.

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This nonsense variant may result in an unpaired Cys residue (with the potential to mediate dimerization). However, unlike some other variants (missense), this nonsense variant forms dimers that are difficult to distinguish from full-length TIMP3 when exogenously expressed in COS-7 cells (Figure 5). Reverse zymography also indicates retained activity as a metalloproteinase inhibitor. The molecular weight is consistent with the prediction that the premature stop codon removes the C-terminal site for N-glycosylation. This lower molecular weight (unglycosylated) species is unique to the variant and is not seen in the wild-type condition (Fig. 5).

Case#: Marlhens_1997_Patient_III-2, female, age 20 years at time of report, unspecified ethnicity

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0000580 (Pigmentary retinopathy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0001141 (Severely reduced visual acuity)

CaseHPOFreeText: Pigmentary deposits, Attenuation of retinal blood vessels, and Optic disc pallor were all mild/moderate.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All RPE65 coding exons and flanking sequences were PCR-amplified and subjected to single-strand conformation analysis. Exon 10 was identified as a likely candidate to harbor a variant.

CaseMethod1: Sanger sequencing of all 14 exons of RPE65

CaseMethod2: Screening of PCR products using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant

CaseGenotypingMethod: All 14 exons of RPE65 were PCR-amplified and subjected to Sanger sequencing. Screening of PCR products was also performed using SSCA for the maternal variant and AlwNI restriction digest for the paternal variant.

Variant: Affected individuals are compound heterozygous for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) (maternal) and NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) (paternal) variants.

ClinVar: 98821, 13114

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1067del (p.Asn356fs) variant is 0.00005458 (within the East Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903930-AT-A The maximum allele frequency for the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant is 0.00008676 (within the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68905269-G-A

VariantEvidence: The maternal frameshift variant occurs in exon 10 of 14 and is predicted to either trigger NMD or disrupt 33% of the protein product. The paternal nonsense variant occurs in exon 7 of 14 and is predicted to either trigger NMD or truncate 56% of the protein product. Both are likely to be null variants.

CaseAddInfo: The two variants were confirmed to be in trans, and heterozygous carriers were found to be unaffected. Potential parental consanguinity was not mentioned.

CasePMIDs: N/A

Case#: Gu_1997_Family_PMK30_Patient_V-5, male, unknown age, Indian ethnicity

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000505 (Visual impairment), HP:0008047 (Abnormality of the vasculature of the eye), HP:0000648 (Optic atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers.

CaseMethod1: PCR products were screened by single-strand conformation polymorphism (SSCP) analysis.

CaseMethod2: Sanger sequencing of all RPE65 exons

CaseGenotypingMethod: After discovery of a band shift for exon 10, the patient sample was subjected to PCR and Sanger sequencing of all RPE65 exons.

Variant: Affected individuals are homozygous for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant.

ClinVar: 13117 (homozygous)

gnomAD: The maximum allele frequency for the NM_000329.3(RPE65):c.1087C>A (p.Pro363Thr) variant is 0.0001307 (within the South Asian population, with no homozygotes). https://gnomad.broadinstitute.org/variant/1-68903911-G-T

VariantEvidence: A different publication (PMID: 16828753) later used QBI-293A cells to establish that this variant decreases the stability of the RPE65 protein, shifts its localization from predominantly in the membrane fraction to predominantly in the cytosolic fraction, and abolishes its isomerohydrolase activity.

CaseAddInfo: The family pedigree shows consanguinity in the parents of all affected individuals.

CasePMIDs: N/A

Case#: DiBenedetto_Patient_1, male, age 74 at time of evaluation, Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side

CasePresentingHPOs: HP:0000575 (Scotoma), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0000822 (Hypertension), HP:0001342 (Cerebral hemorrhage), HP:0001397 (Hepatic steatosis), HP:0009726 (Renal neoplasm), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007894 (Hypopigmentation of the fundus)

CaseHPOFreeText: Onset in 5th decade of life, anterior chamber intraocular lenses in both eyes (shown by slit lamp examination), bilateral cataract surgery at age 60, stroke at age 71, renal tumor at age 74, visual acuity limited to hand motion at age 74, initial diagnosis not with SFD but with retinitis pigmentosa.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0025574 (Macular hemorrhage), HP:0030496 (Macular exudate),

CaseNotHPOFreeText: Features of syndromic retinal dystrophy

CasePreviousTesting: Limited (non genome-wide) genetic testing confirming absence of pathogenic variants in 13 different genes; RHO, PRPH2/RDS, RP1, IMPDH1, PRPF31, PRPF, PRPF8, NR2E3, SNRNP200, TOPORS, KLHL7, RPGR, and RP2.

CaseMethod1: Limited genetic testing for 13 candidate genes

CaseMethod2: N/A

CaseGenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel

Variant: NM_000362.5(TIMP3):c.410A>G (p.Tyr137Cys)

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

VariantEvidence: The variant is a missense substitution at a conserved amino acid. A homology model (based on an available TIMP2 crystal structure) indicates that the variant is a more hydrophobic substitution at a surface-exposed site. This may disrupt protein-protein interactions, particularly with EFEMP1, which is known to interact with the region.

CaseAddInfo: The proband has a number of family members diagnosed with retinitis pigmentosa (son, sister, brother, mother, maternal grandmother, and maternal great-uncle ). The pattern was consistent with autosomal dominant inheritance. His sister underwent treatment for choroidal neovascularization at age 73.

CasePMIDs: N/A

Case#: Yzer_2006_Patient_22018, male, age 2 months at diagnosis, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0001483 (Eye poking), HP:0002457 (Abnormal head movements), HP:0030553 (Visual acuity no light perception), HP:0000543 (Optic disc pallor), HP:0000639 (Nystagmus), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. No perception of light was detected at age 2.5 years. Pupils were wide and minimally responsive to bright light.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology)

CaseNotHPOFreeText: Most recent fundus examination was relatively normal at 3 years of age.

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was not confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Narumi_2010_patient_3, male, age 10 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000939 (Osteoporosis), HP:0011463 (Childhood onset), HP:0000572 (Visual loss), HP:0000639 (Nystagmus), HP:0000541 (Retinal detachment), HP:0004327 (Abnormal vitreous humor morphology, vascular remnants), HP:0008046 (Abnormal retinal vascular morphology), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0020110 (Bone fracture), HP:0001388 (Joint laxity), HP:0001252 (Hypotonia), HP:0007083 (Hyperactive patellar reflex), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. In one eye, peripheral retinal vessel was insufficiently developed and optic disc traction was observed. Complete blindness occurred at age 3 due to deterioration of abnormal vascular growth in one eye.

CaseNotHPOs: N/A

CaseNotHPOFreeText: No deformity of long bones was observed.

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus.

CaseMethod1: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1145C>T (p.Pro382Leu) and NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variants in the compound heterozygous state.

ClinVar: 40288, 40290

gnomAD: The NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) variant is found in gnomAD v2.1.1 at a frequency of 0.000008800 (1/113634) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68153913-C-T The NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LR5P5):c.1145C>T (p.Pro382Leu) is a missense variant that does not have evidence of impact on the protein product, although it has been observed in the compound heterozygous state in an apparently unrelated proband from this same study. NM_002335.4(LRP5):c.4600C>T (p.Arg1534Ter) is a nonsense variant in exon 23 of 23 and is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 5% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the p.Arg1534Ter variant (mother), and one of whom carries the p.Pro382Leu variant (father)

CasePMIDs: N/A

Case#: Weisschuh_2018_Patient_8, sex unreported, age 35 years at time of report, likely from Europe or of European descent

CasePresentingHPOs: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia)

CaseHPOFreeText: The proband has been previously diagnosed with achromatopsia.

CaseNotHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously genotyped by Sanger sequencing of CNGB3, CNGA3, and GNAT2.

CaseMethod1: next-generation sequencing of PDE6C and possibly other loci

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: The proband has been genotyped by Sanger sequencing of CNGB3, CNGA3, GNAT2, and PDE6C, as well as next-generation sequencing of PDE6C and possibly other loci.

Variant: The proband harbors the NM_006204.4(PDE6C):c.78del (p.Lys27fs) and NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) variants in the compound heterozygous state.

ClinVar ID: 487693, 487691

gnomAD: The NM_006204.4(PDE6C):c.78del (p.Lys27fs) variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00001759 (2/113724) in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95381740-C-T

VariantEvidence: NM_006204.4(PDE6C):c.775C>T (p.Arg259Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 70% of the protein product. NM_006204.4(PDE6C):c.78del (p.Lys27fs) is a frameshift variant in exon 1 of 12 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 97% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Jiang_2015_Patient_010043, female, age 28 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0030329 (Retinal thinning), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to clinical phenotyping.

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus. Parents were implied to have been genotyped as well. The patient and family members were subjected to additional genotyping through restriction fragment length polymorphism analysis, then confirmation by HhaI restriction endonuclease digestion of PCR products from the relevant exon 13.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) variant in the heterozygous state.

ClinVar: 9357

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The variant has been reported in an apparently unrelated family from this same publication. The p.Arg838His substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: The proband's parents are unaffected and negative for the variant, indicating that this may be a de novo case. It is uncertain whether genotyping methods were sufficient to confirm paternity and maternity.

CasePMIDs: N/A

Case#: Kajiwara_1993_Proband_III-1, male, age 59 years at time of report, family origin not reported

CasePresentingHPOs: Adult onset HP:0003581, Nyctalopia HP:0000662, Reduced visual acuity, HP:0007663, Foveal hyperpigmentation HP:0008001, Foveal atrophy HP:0025010, Subretinal deposits HP:0031528, Uveitis HP:0000554, Cataract HP:0000518, Corneal opacity HP:0007957, Central scotoma HP:0000603, Chorioretinal atrophy HP:0000533, Optic disc pallor HP:0000543

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa albescens, with age of reported onset after 40 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing of this family consisted of screening of the RHO locus for variants causing RP, with negative results. Genotyping started with single strand conformation polymorphism analysis of PCR-amplified products from the PRPH2 gene, followed by Sanger sequencing of the relevant PCR product to identify the variant. SSCP was subsequently performed to genotype family members..

Variant: The proband harbors the NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) variant in the heterozygous state.

ClinVar ID: 98707

gnomAD: The NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.73_74del (p.Trp25fs) is a frameshift variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.

CaseAddInfo: The proband's family includes a daughter who is an "unaffected" (subclinically affected) carrier of the variant with an elevated dark-adapted threshold and numerous yellow/white subretinal flecks in the periphery of the fundus with macular sparing.

CasePMIDs: N/A

Case#: Wang_2021_Patient_III-1, male, 32 years old, ethnicity described as Chinese

CasePresentingHPOs: HP:0000533 (Chorioretinal atrophy), HP:0007754 (Macular dystrophy), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0001123 (Visual field defect), HP:0007994 (Peripheral visual field loss), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000551 (Color vision defect), HP:0030534 (Abnormal best corrected visual acuity test), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: The proband has been diagnosed with cone-rod dystrophy, with the family exhibiting X-linked pattern of inheritance.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and was subjected to whole-exome sequencing.

CaseMethod1: Whole-exome sequencing

CaseMethod2: Sanger sequencing to confirm candidate variants within the RPGR locus

CaseGenotypingMethod: The proband and was subjected to whole-exome sequencing, followed by Sanger sequencing to confirm candidate variants within the RPGR locus and to genotype family members.

Variant: The proband harbors the NM_001034853.2(RPGR):c.2383G>T (p.Glu795Ter) variant in the hemizygous state.

ClinVar: 975145

gnomAD: The variant was not found in gnomAD v.2.1.1.

VariantEvidence: NM_001034853.2(RPGR):c.2383G>T (p.Glu795Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay but truncates ~31% of the C-terminus of the protein product. In HEK-293T cells, truncation was confirmed by western blotting (Figure 3b), yet immunocytochemistry showed normal (cytoplasmic) localization (Figure 3c).

CaseAddInfo: The proband is a member of a family with three other affected males and three carrier females described as unaffected.

CasePMIDs: N/A

Case#: 4, Male, Han Chinese

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)

CaseHPOFreeText: Skeletal Deformities

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)

Variant1: c.792+1G>T

Variant1ClinVarID: N/A

Variant1CAID: CA355962278

Variant2: c.792+1G>T

Variant2ClinVarID: N/A

Variant2CAID: CA355962278

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 1, Male, Han Chinese

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)

CaseHPOFreeText: Skeletal Deformities

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)

Variant1: c.1190-1G>A

Variant1ClinVarID: 1204494

Variant1CAID: CA355963511

Variant2: Not Identified

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 8, Male, Han Chinese

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)

CaseHPOFreeText: Skeletal Deformities

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)

Variant1: c.792+1G>T

Variant1ClinVarID: N/A

Variant1CAID: CA355962278

Variant2: Not identified

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 4, 11 years old, Iranian

DiseaseAssertion: MPS1-H (Severe)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity not detected

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1029C>A (p.Y343X)

Variant1ClinVarID: 222997

Variant1CAID: CA356984

Variant2: c.1029C>A (p.Y343X)

Variant2ClinVarID: 222997

Variant2CAID: CA356984

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, 4 years old, Iranian

DiseaseAssertion: MPS1-H (Severe)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity not detected

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#: P13, Female, 2.7 years (diagnosed), 5.1 (report), 18 kg (weight), 96 cm (height), Algerian

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0002240, HP:0001387, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatomegaly, Hernia(Ombelical), Corneal Opacity, Hydrocephalus)

CaseHPOFreeText: Chronic Rhinorrhea

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac Manifestations

CaseEnzymeAssay: IDUA Enzyme activity 2 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 19.6 (fold change to the reference range mean according to age)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

Variant1: c.501C>G (p.Tyr167*)

Variant1ClinVarID: 92644

Variant1CAID: CA220511

Variant2: c.501C>G (p.Tyr167*)

Variant2ClinVarID: 92644

Variant2CAID: CA220511

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 17 (see Table 2), 40 weeks (Gestational age)

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 2 (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: Upper respiratory tract involvement

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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 (see Table 2), 33 weeks, 1 day (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.44 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

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

Variant2ClinVarID: 222995

Variant2CAID: CA356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 29 (see Table 2), 40 weeks, 5 days (Gestational age)

DiseaseAssertion: MPS1-S

FamilyInfo: Sibling of Patient 28 (see Table 2)

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 1.61 nmol x mg-1 × hr-1

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

PMID: 23837464

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 20 (see Table 2), 37 weeks, 1 day (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Sibling of Patient 19 (see Table 2)

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 0.95 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.1044C>A (p.N348K)

Variant2ClinVarID: N/A

Variant2CAID: CA:355963142

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9 (see Table 2), 37 weeks, 2 days (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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

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

Variant2ClinVarID: 222995

Variant2CAID: CA:356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 21 (see Table 2), 41 weeks, 2 days (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 0.35 nmol x mg-1 × hr-1

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 222995

Variant1CAID: CA356986

Variant2: c.943G>T (p.D315Y)

Variant2ClinVarID: N/A

Variant2CAID: CA:355962740

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 18 (see Table 2), 40 weeks (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.77 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.1513C>G (p.R505G)

Variant2ClinVarID: 1482722

Variant2CAID: CA:355964784

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 28 (see Table 2), 40 weeks, 5 days (Gestational age)

DiseaseAssertion: MPS1-S

FamilyInfo: Sibling of Patient 29 (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.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 13 (see Table 2), 38 weeks, 3 days (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: 0.43 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.653T>C (p.L218P)

Variant2ClinVarID: 222995

Variant2CAID: CA:356986

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Subject 1, female, in her 30s (age at enrollment), died during extension study from pneumonia and respiratory failure sixty-five days after her first dose in the extension study.

DiseaseAssertion: MPS1-HS

FamilyInfo: N/A

CasePresentingHPOs: HP:0002093, HP:0002540, HP:0002090, HP:0002176 (Chronic respiratory insufficiency, inability to walk, pneumonia, spinal cord compression)

CaseHPOFreeText: Hemidiaphragmatic paralysis, improved strength and range of motion

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Enzyme replacement therapy with laronidase

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: II-2, Female, 2 years (onset), Chinese

DiseaseAssertion: MPS 1

FamilyInfo: I-1 and I-2 are the parents, II-4 is a full sibling of II-2 and a full child of I-1 and I-2. II-4 also carries the disease. (pedigree is figure # 1).

CasePresentingHPOs: HP:0001367, HP:0000622, HP:0007663, HP:0001718, HP:0001643, HP:0001698, HP:0000238, (Abnormal joints, Blurred vision, Decreased vision, Mitral stenosis (severe), Patent ductus arteriosus (tubular), Pericardial effusion (moderate), Hydrocephalus)

CaseHPOFreeText: Abnormal mitral valve development, Anterior mitral valve prolapses and insufficiency (moderate), Pulmonary hypertension (moderate), Bilateral temporal arachnoid cyst, Congenital spinal stenosis, Congenital glaucoma, Corneal gray degeneration, Corneal staphyloma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: c.1037T>G

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.18115dupT

Variant2ClinVarID: 1454082

Variant2CAID: CA2573137507

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient D4, Druze religious group, located in lower Galilee.

DiseaseAssertion: N/A

FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

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.1096A>C (p.T366P)

Variant1ClinVarID: 11916

Variant1CAID: CA:256117

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient D1, Druze religious group, located in lower Galilee.

DiseaseAssertion: MPS1-H

FamilyInfo: Both parents, as well as an aunt and uncle who had a deceased affected child, were heterozygous for the same mutation.

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.192C>A (p.Y64X)

Variant1ClinVarID: 11914

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 19, Female, infancy (onset), 3 years (diagnosed), 17 years (report)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: N/A

CasePresentingHPOs: HP:0004322, HP:0001387, HP:0002240, HP:0001744, HP:0001537, HP:0001007, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Joint Stiffness, Hepatomegaly (severe), Splenomegaly(severe), Umbilical Hernia, Hirsutism, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: (Mental Development (delayed), Systolic murmur 3/6/combined defect of mitral valve)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.H539T (fsX21)

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.1650+5G>A (splicing error)

Variant2ClinVarID: 92634

Variant2CAID: CA220504

AdditionalVariants: p.A8, p.A20, p.Q33H

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 18, Male, 15 years (onset), 15 years (diagnosed), 15 years (report)

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Patients 17 and 18 are siblings

CasePresentingHPOs: HP:0004322, HP:0001387, HP:0002240, HP:0001744, HP:0001537, HP:0000280, HP:0000943 (Short Stature, Joint Stiffness, Hepatomegaly (moderate), Splenomegaly(mild), Umbilical Hernia, Coarse Facial Features (mild), Dysostosis Multiplex)

CaseHPOFreeText: (Mental Development (developmental quotient 93 at 15y, Verbal IQ 77; CIQ 79), Umbilical/Carpal Tunnel Syndrome)

CaseNotHPOs: HP:0000256 (Macrocephaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.Q380R

Variant1ClinVarID: 550799

Variant1CAID: CA2802202

Variant2: p.Q380R

Variant2ClinVarID: 550799

Variant2CAID: CA2802202

AdditionalVariants: p.A8/A8, p.A20/A20

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 7, Female, 8 months (onset), 10 months (diagnosed), 5 years (report)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0000256, HP:0001387, HP:0002240, HP:0001537, HP:0000486, HP:0002857, HP:0012185, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly (at 8m), Joint Stiffness (at 8m), Hepatomegaly (Severe before HSCT, mild after HSCT), Umbilical Hernia, Strabismus, genua valga, carpal tunnel syndrome, Coarse Facial Features (very mild), Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (developmental quotient 110 at 1y, Developmental quotient 115 at 5y), Normal psychomotor development, Hearing problems,

CaseNotHPOs: HP:0004322, HP:0001744 (Short Stature, Splenomegaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: normal IDUA activity in leucocytes (4 years after HSCT)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation at 1y

GenotypingMethod: Not Provided

Variant1: p.W402X

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1650 + 5G > A

Variant2ClinVarID: 92634

Variant2CAID: CA220504

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 8, Male, 2, 5 years (onset), 3,5 months (diagnosed), 16 years (report)

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0000256, HP:0001387, HP:0002240, HP:0001744, HP:0001537, HP:001285, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly, Joint Stiffness, Hepatomegaly (mild before HSCT), Splenomegaly (mild before HSCT), Umbilical Hernia, Carpal tunnel syndrome, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Borderline developmental quotient at 3y, IQ 117 at 12y)

CaseNotHPOs: HP:0004322, HP:0002240, HP:0001744 (Short Stature, Hepatomegaly (after HSCT), Splenomegaly (after HSCT))

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: normal IDUA activity at 16 years

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation at 5y

GenotypingMethod: Not Provided

Variant1: p.W402X

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: p.E640fs

Variant2ClinVarID: 558359

Variant2CAID: CA355966048

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 14, Male, 24 months (onset), 3 years (diagnosed), 8 years (report), deceased (at 9y)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0004322, HP:0000256, HP:0001387, HP:0002240, HP:0001744, HP:0001638, HP:0000023, HP:0002415, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Macrocephaly, Joint Stiffness, Hepatomegaly (severe), Splenomegaly (moderate), Cardiomyopathy (involvement of valves), Inguinal Hernia, Leukodystrophy (in MRI), Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: (Mental Development (Delayed since infancy), Vision and Hearing impairment, Ear Inflammations, Cervical Canal Stenosis (in MRI at 7y), Tracheostomy)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.W626X

Variant2ClinVarID: 928997

Variant2CAID: CA355965968

AdditionalVariants: p.Q33H/Q33H, p.L118

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 12, Female, 5 months (onset), 5 years (diagnosed), 5 years (report), deceased (at 7y)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0004322, HP:0000256, HP:0001387, HP:0002240, HP:0001744, HP:0001537, HP:0000365, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Macrocephaly, Joint Stiffness, Hepatomegaly (Severe), Splenomegaly (moderate), Umbilical Hernia, Deafness (progressive), Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Delayed)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.D315Y

Variant2ClinVarID: N/A

Variant2CAID: CA355962740

AdditionalVariants: p.A8, p.A20, p.Q33H, p.L118

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 9, Female, 3-4 years (onset), 4 years (diagnosed), 20 years (report), deceased (accidentally at 21y)

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0000256, HP:0001387, HP:0002240, HP:0001744, HP:0001639, HP:001285, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly, Joint Stiffness (Severe and progressive), Hepatomegaly (Severe at diagnosis but none at report), Splenomegaly (mild at diagnosis and report), Hypertrophic Cardiomyopathy (Progressive), Carpal tunnel syndrome, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Uneven Development at 2y; IQ 117 at 12y)

CaseNotHPOs: HP:0004322 (Short Stature)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: ERT since 18y

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.W402X

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: p.E640fs

Variant2ClinVarID: 558359

Variant2CAID: CA355966048

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 20, Female, infancy (onset), 2 years (diagnosed), 2 years (report)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: N/A

CasePresentingHPOs: HP:0004322, HP:0002240, HP:0001744, HP:0000280, HP:0000943, HP:0007957 (Short Stature, Hepatomegaly, Splenomegaly, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: (Mental Development (delayed since early infancy), Mild LV hypertrophy, Frequent respiratory infections, Vision Impairment and Hearing Loss)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Not Provided

Variant1: p.V620F

Variant1ClinVarID: 1067173

Variant1CAID: CA355965934

Variant2: p.V620F

Variant2ClinVarID: 1067173

Variant2CAID: CA355965934

AdditionalVariants: p.R105Q/R105Q, p.N181/N181, p.A314/A314, p.A361T/A361T, p.T388/T388, p.T410/T410, p.V454I/V454I, p.R489/R489

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 55, 6 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

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.589G>A (p.Gly197Ser)

Variant1ClinVarID: 1526094

Variant1CAID: CA355961839

Variant2: c.1091C>T (p.Thr364Met)

Variant2ClinVarID: 11925

Variant2CAID: CA256126

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 16, 2 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, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.3% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.568_581del (p.Asn190Hisfs*204)

Variant1ClinVarID: 3639714

Variant1CAID: CA2801994

Variant2: c.568_581del (p.Asn190Hisfs*204)

Variant2ClinVarID: 3639714

Variant2CAID: CA2801994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, 2 years old (age at report), male, 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: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.343G>T (p.Asp115Tyr)

Variant1ClinVarID: N/A

Variant1CAID: CA355961128

Variant2: c.343G>T (p.Asp115Tyr)

Variant2ClinVarID: N/A

Variant2CAID: CA355961128

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 21, 2 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.9% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.935G>A (p.Trp312Ter)

Variant1ClinVarID: N/A

Variant1CAID: CA355962697

Variant2: c.935G>A (p.Trp312Ter)

Variant2ClinVarID: N/A

Variant2CAID: CA355962697

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 11, 4 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of patient 10

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.6% (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 39, 1 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Joint contractures, dysostosis multiplex (HP:0002828, HP:0000943)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.4% (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 53, 2 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, corneal clouding, recurrent infections, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0001249, HP:0100790)

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.502G>T (p.Gly168Ter)

Variant1ClinVarID: N/A

Variant1CAID: CA355961652

Variant2: c.1402+1G>A

Variant2ClinVarID: 555490

Variant2CAID: CA355964379

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 19, 1 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: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.784delC (p.His262Thrfs*55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

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

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 49, 2 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, recurrent infections, dysostosis multiplex, hernia (HP:0000280, HP:0001433, HP:0002719, HP:0000943, HP:0100790)

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.(1189+1)(1190–1)(1959_?)del in the paper, unsure how to write this in current nomenclature.

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.(1189+1_1190-1)(2003?)del in the paper, unsure how to write this in current nomenclature.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 47, 2 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 1.8% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.(792+1_793-1)_(972+1_973-1)del in the paper, unsure how to write this in current nomenclature.

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.(792+1_793-1)_(972+1_973-1)del in the paper, unsure how to write this in current nomenclature.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 46, 9 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1898C>T (p.Ser633Leu)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.1898C>T (p.Ser633Leu)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 36, 6 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, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

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.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#: Case 2, proband was an 2-year-old female of Mexican origin. She was born at full term via cesarian section at 7 lbs and 6 oz.

DiseaseAssertion: MPS1-H

FamilyInfo: Proband came from a consanguineous union (uncle-niece). Case 1 is the proband's brother.

CasePresentingHPOs: Recurrent otitis media (HP:0000403)

CaseHPOFreeText: She also had more than 10 ear infections, and was diagnosed with bilateral moderate to severe hearing loss. She was mildly delayed, mainly in language.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Her physical growth was not impaired.

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Given the conclusion to discontinue enzyme replacement therapy in her brother, the decision was made, again with the participation of the patient's mother, not to initiate ERT unless she developed somatic symptoms that could be alleviated with treatment.

CaseBMT: N/A

Variant1: c.923T>C (p.L308P)

Variant1ClinVarID: 502243

Variant1CAID: CA2802119

Variant2: c.923T>C (p.L308P)

Variant2ClinVarID: 502243

Variant2CAID: CA2802119

AdditionalVariants: Shee also had a homozygous variant (c.268G>A) in the SGSH gene, and additionally diagnosed with Sanfilippo syndrome type A.

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Case 1, proband was an 8-year-old male of Mexican origin. He was born at 32 weeks gestational age; 3 lbs and 12 oz. He was diagnosed at 1.5 years old.

DiseaseAssertion: MPS1-H

FamilyInfo: Proband came from a consanguineous union (uncle-niece). Case 2 is the proband's sister.

CasePresentingHPOs: Developmental delay, coarse facial features, gastroesophageal reflux, hiatal hernia, umbilical hernia, recurrent otitis media, hepatomegaly, dysostosis multiplex, joint stiffness (HP:0001263, HP:0000280, HP:0002020, HP:0002036, HP:0001537, HP:0000403, HP:0002240, HP:0000943, HP:0001387)

CaseHPOFreeText: He had bilateral moderate to severe hearing loss. He had a normal ophthalmologic examination at 3 years of age, and at age 8 has not developed corneal clouding. He had contractures at the knees as well.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Enzyme analysis on fibroblasts showed 10% residual alpha-l-iduronidase activity and no detectable activity for heparan N-sulfatase.

CaseUrineGAGs: Urinary quantitation of glycosaminoglycans showed 127 mg/g creatinine of uronic acid by the orcinol reaction (nl. 10.7 ± 8.0) and 449 mg/g creatinine by the carbazole reaction (nl. 16.9 ± 9.9), giving a carbazole to orcinol ratio of almost 3, which is indicative of excess heparan sulfate as compared with dermatan sulfate. The electrophoresis which revealed a strong band of heparan sulfate and slightly less chondroitin sulfate was confirmatory of this conclusion. N-sulfated hexosamine was 126 mg/g creatinine (nl. 15.8 ± 12).

CaseERT: He was started on enzyme replacement therapy (ERT) for iduronidase deficiency at age 3 years. However, his severe hyperactivity often precluded therapy as he could not sit still during the infusions, and the intravenous access catheter infiltrated on numerous occasions. Given his mild somatic symptoms, the concurrent diagnosis of Sanfilippo syndrome, a lethal condition, as well as the difficulty his family had with his complex medical care, the decision was made with the family's participation and accord to discontinue ERT and to treat only those problems that would improve his quality of life. He was on ERT for a total of 3 years.

CaseBMT: He was evaluated for a bone marrow transplant but was determined to be ineligible due to his low developmental quotient.

Variant1: c.923T>C (p.L308P)

Variant1ClinVarID: 502243

Variant1CAID: CA2802119

Variant2: c.923T>C (p.L308P)

Variant2ClinVarID: 502243

Variant2CAID: CA2802119

AdditionalVariants: He also had a homozygous variant (c.268G>A) in the SGSH gene, and additionally diagnosed with Sanfilippo syndrome type A.

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 50, male, Han origin, 5 years 6 months old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.8 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: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 55, female, Han origin, 2 years 3 months old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Mongolian macula, Hernia, Airway obstruction (HP:0011369, HP:0100790, HP:0006536)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.0 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.503G>T (p.G168V)

Variant2ClinVarID: 4069658

Variant2CAID: CA355961655

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 42, male, Han origin, 2 years 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 1.0 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.1402+1G>T

Variant1ClinVarID: 1323099

Variant1CAID: CA355964387

Variant2: c.1402+1G>T

Variant2ClinVarID: 1323099

Variant2CAID: CA355964387

AdditionalVariants: N/A

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

PreviouslyPublished N/A

Case#: Patient 26, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

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: 668insGCG, it looks like this should be c.665_667dup

Variant1ClinVarID: N/A

Variant1CAID: CA2586965942

Variant2: c.236C>T (p.A79V)

Variant2ClinVarID: 1458769

Variant2CAID: CA356987

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 24, male, Han origin, age not available

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 2.3 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.296+4G>A, it looks like this is a typo and should be c.299+4G>A

Variant2ClinVarID: N/A

Variant2CAID: CA2669476183

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, female, Han origin, 2.5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Mongolian macula, Hernia (HP:0011369, HP:0100790)

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.536C>G (p.T179R)

Variant2ClinVarID: 556358

Variant2CAID: CA355961718

AdditionalVariants: N/A

ParentalGenotype: Father - c.236C>T, Mother - c.536C>G. The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 11, male, Han origin, 7 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/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 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA234128

Variant2: c.236C>T (p.A79V)

Variant2ClinVarID: 1458769

Variant2CAID: CA234128

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 12, female, Han origin, 13 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly (HP:0001387, HP:0001433)

CaseHPOFreeText: Cardiac disease

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

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.0 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.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.536C>G (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

ParentalGenotype: Father - c.536C>G, Mother - c.536C>G. 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 7, female, Han origin, 7 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Mongolian macula, Hernia, Airway obstruction (HP:0011369, HP:0100790, HP:0006536)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.3 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.236C>T (p.A79V)

Variant2ClinVarID: 1458769

Variant2CAID: CA356987

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 34, male, Han origin, 10 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 1.2 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.656dupG (Paper refers to the variant as c.657dupG, there is a typo in the article where all duplication variants are one base pair off)

Variant1ClinVarID: N/A

Variant1CAID: CA2586965940

Variant2: c.623G>A (p.G208D)

Variant2ClinVarID: 554590

Variant2CAID: CA355961948

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 44, male, Han origin, 21 years old (age at diagnosis)

DiseaseAssertion: MPS1-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.2T>C (p.Met1Thr)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

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#: P1, male, 1.1 years (age at HCT - hematopoietic cell transplantation), 2 iPS colonies per 100,000 cells (KC)

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: Yes - Donor cells were received from KC, keratinocytes. Study was conducted 0.2 years after HCT.

Variant1: c.501C>G (p.Y167X)

Variant1ClinVarID: 92644

Variant1CAID: CA220511

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.07 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.536C>A (p.T179K)

Variant1ClinVarID: 2734636

Variant1CAID: CA355961717

Variant2: c.536C>A (p.T179K)

Variant2ClinVarID: 2734636

Variant2CAID: CA355961717

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1054T>C (p.F352L)

Variant1ClinVarID: 2432790

Variant1CAID: CA2802178

Variant2: c.1112T>A (p.V371D)

Variant2ClinVarID: 1470032

Variant2CAID: CA355963356

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA220498

Variant2: c.1577T>C (p.L526P)

Variant2ClinVarID: 567566

Variant2CAID: CA2802300

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided.

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1042_1062dup

Variant1ClinVarID: 2432708

Variant1CAID: CA549264534

Variant2: c.986A>G

Variant2ClinVarID: N/A

Variant2CAID: CA2802157

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1051G>A (p.A351T)

Variant1ClinVarID: 967585

Variant1CAID: CA2802176

Variant2: c.497G>C (p.R166T)

Variant2ClinVarID: 1388155

Variant2CAID: CA2801967

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: Not specified

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Not performed

CaseUrineGAGs: Normal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.53T>C (p.L18P)

Variant1ClinVarID: 193062

Variant1CAID: CA238566

Variant2: c.1651G>C (p.V551L)

Variant2ClinVarID: 1410776

Variant2CAID: CA2802341

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A