Case#: Morimura_1998_Family_0748_Patient_II-1, female, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.643+2T>A variant.

ClinVar: 940479 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.643+2T>A variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.643+2T>A is an intron 6 variant strongly predicted to disrupt a canonical splice donor site (with a delta score of 0.98).

CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.

CasePMIDs: N/A

Case#: Hove_2016_Proband_59, sex not reported, onset in early childhood, family ancestry reported as Danish

CasePresentingHPOs: HP:0007750 (foveal hypoplasia)

CaseHPOFreeText: The proband has a diagnosis of Aland Island eye disease and showed foveal hypoplasia in both eyes (supplement 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping may have been limited to Sanger sequencing of PCR products from the CACNA1F gene, or may have performed screening of other known genes associated with this phenotype.

CaseMethod1: Sanger sequencing of CABP4

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible panel-based sequencing of other inherited retinal disease-associated genes.

Variant: The individual harbors the NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) variant in the homozygous state.

ClinVar ID: 636004

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.000001695 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67458492-A-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) is a missense variant that does not have a characterized functional impact on CABP4..

CaseAddInfo: No details are available regarding the potential for parental consanguinity.

CasePMIDs: N/A

Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2

CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.

ClinVar ID: 865751

gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has an affected sibling who also harbors the variant.

CasePMIDs: N/A

Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 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 visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. 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.

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.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Perrault_2000_Family_11_Proband, FEmale, age unknown, family origin in Algeria with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: N/A

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1

VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case#: Perrault_2000_Family_12_Proband, Female, age unknown, family origin in Tunisia with Arab ancestry

CasePresentingHPOs: N/A

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)

CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons

CaseMethod2: Single strand conformational polymorphism analysis

CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by SSCP and by Sanger sequencing of PCR products from all 20 exons of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant.

ClinVar: 98607

gnomAD: The variant is absent from gnomAD version 2.1.1.

VariantEvidence: The NM_000180.4(GUCY2D):c.622del (p.Arg208GlyfsTer8) variant is predicted to trigger nonsense mediated decay or to disrupt ~81% of the protein product by frameshift.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case: Gliem_2000_Family_3_patient_III.5, male, country of origin Germany, onset at 31 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Relatively early presentation at age 31 with nyctalopia and prolonged dark adaptation. Evaluation at age 56 showed widespread central and peripheral atrophy, central fibrosis, and reduced choroidal thickness.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Targeted next-generation sequencing of the proband (for a 74-gene panel of retinal dystrophy genes), identifying the TIMP3 variant as well as a heterozygous c.1107G>A (p.Trp369) variant in RP1L1*

GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.452A>G (p.Tyr151Cys) missense variant.

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Case#: Gong_2001_Proband_3, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.

CaseMethod1: Linkage analysis with additional markers around a strong candidate marker

CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus

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

Variant: The patient harbors the NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant in the homozygous state.

ClinVar: 6270

gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Riazuddin_2006_61021_patient_12, female, age 33 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61021 harbor the NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) variant in the homozygous state.

CAID: CA2573332091

gnomAD: This variant is absent from gnomAD v2.1.1.

VariantEvidence: NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) is a frameshift variant in exon 17 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~19% of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

Case#: Perez-Roustit_2017_Proband, male, age 31 years, family ethnic origin not reported

CasePresentingHPOs: Nystagmus HP:0000639, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Presenile cataracts HP:0007819, Pigmentary retinopathy HP:0000580, Patchy atrophy of the retinal pigment epithelium HP:0007791, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype included increased retinal thickness and presence of hyper-reflective formations around the optic disc and periphery. Visual impairment was severe but did not evolve significantly during the first 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by screening for ABCA4 variants.

CaseMethod1: Sanger sequencing of the ABCA4 gene

CaseMethod2: Sanger sequencing of the KCNJ13 exons and intron-exon boundaries

CaseGenotypingMethod: The proband was previously genotyped by screening for ABCA4 variants, followed by Sanger sequencing of the KCNJ13 exons and intron-exon boundaries.

Variant: The individual is compound heterozygous with the maternal NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) and paternal NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variants.

ClinVar: 978434, 978433

gnomAD: The NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) variant was not found in gnomAD version 4.1.0. The NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) variant is found in gnomAD version 4.1.0 at a frequency of 0.00002669 (2/74924) in the African / African-American population https://gnomad.broadinstitute.org/variant/2-232768619-G-A?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.314G>T (p.Ser105Ile) is a missense variant that has no experimental evidence in this study. NM_002242.4(KCNJ13):c.655C>T (p.Gln219Ter) is a nonsense variant in exon 3 of 3 that is not predicted to trigger NMD but rather to truncate the C-terminal 39% of the protein product.

CaseAddInfo: The proband's family history is not known to include parental consanguinity or history of retinal disease.

CasePMIDs: N/A

Case#: Gu_1997_Patient_arRP341-II-1, female, age 3 months at onset, German ethnicity

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0003593 (Infantile onset), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007663 (Reduced visual acuity)

CaseHPOFreeText: The first detectable phenotype was observed at age 3 months, when no reactions to objects or faces were observed. Rod ERG was extinguished at age 8 months, while cone ERG flicker response was significantly decreased. Low visual acuity was found at age 3 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.

CaseMethod1: PCR amplification and Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.

Variant: The patient is a compound heterozygote with the NM_000329.3(RPE65):c.11+5G>A (paternal) and NM_000329.3(RPE65):c.89dup (p.Thr31fs) (maternal) variants in trans.

ClinVar: 98825, 98898

gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T The NM_000329.3(RPE65):c.89dup (p.Thr31fs) variant was not found in gnomAD.

VariantEvidence: The paternal variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site. The maternal variant is located within exon 2 and encodes a frameshift predicted to truncate approximately 94% of the protein product.

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

CasePMIDs: N/A

Case#: Allikmets_1997_Proband_1, female, age described as between 55 and 70 years at time of diagnosis, family origin not reported

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration)

CaseHPOFreeText: The proband has been diagnosed with age-related macular degeneration. She belongs to a cohort in which most AMD cases were diagnosed with dry rather than wet AMD, with a broad range of phenotypes including; drusen in the macular and/or peripheral retina and macular / RPE atrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of ABCA4

CaseGenotypingMethod: The proband and her family members have been genotyped by SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation of the variant.

Variant: The proband harbors the NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) variant in the heterozygous state.

ClinVar ID: 99466

gnomAD: The variant was not found in gnomAD v4.1.0.

VariantEvidence: NM_000350.3(ABCA4):c.6519_6529del (p.Lys2175fs) is a frameshift variant in exon 48 of 50 that is predicted to trigger nonsense-mediated decay (or to truncate the C-terminal 4.4% of the protein product.

CaseAddInfo: The proband is the mother of a patient with a diagnosis of Stargardt disease. Her husband and brother-in-law have similarly been diagnosed with age-related macular degeneration between ages 55 and 70 years, but do not have an identified ABCA4 variant.

CasePMIDs: N/A

Case#: El-Haig_2014_Proband, female, age not specified, family origin reported to be Egyptian

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), HP:0007787 (Posterior subcapsular cataract), HP:0010923 (Anterior subcapsular cataract), HP:0000505 (Visual impairment), HP:0007703 (Abnormality of retinal pigmentation), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with cone-rod dystrophy, with the family showing an autosomal recessive mode of inheritance.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing.

CaseMethod1: Next-generation sequencing panel

CaseMethod2: Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions

CaseGenotypingMethod: The proband and her family were initially genotyped by IROme, which generates a hybridization-based DNA library of the 64 most frequently mutated genes in retinal dystrophy, then analyzes it by high-throughput sequencing. Sanger sequencing of ADAM9 exon 14 and flanking exon-intron junctions was then performed.

Variant: The proband harbors the NM_003816.3(ADAM9):c.1396-2A>G variant in the homozygous state.

ClinVar: 189795

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

VariantEvidence: NM_003816.3(ADAM9):c.1396-2A>G is a variant disrupting a canonical splice site in intron 13, which is predicted but not confirmed to disrupt mRNA splicing.

CaseAddInfo: The proband is from a consanguineous family and has two affected sons who are also homozygous for the variant, as well as five unaffected heterozygous family members.

CasePMIDs: N/A

SRF1186

Case#: Parry_2009_Family_MOL0172_patient_IV:3, male, age not specified, family origin reported to be Tunisian Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.

CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.

CaseMethod1: Autozygosity mapping

CaseMethod2: Sanger sequencing

CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.

Variant: The proband harbors the NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) variant in the homozygous state.

ClinVar: 6878

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

VariantEvidence: NM_003816.3(ADAM9):c.490C>T (p.Arg164Ter) is a nonsense variant in exon 6 of 21, and is therefore predicted to result in nonsense-mediated decay.

CaseAddInfo: The proband's family is known to be consanguineous, with the father being the mother's uncle (pedigree shown in Figure 2).

CasePMIDs: N/A

Case#: Lazar_2014_Family_MOL0508_Patient_III:1, female, age 25 at time of report, national origin in Israel, ethnicity listed as Ashkenazi Jewish

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0000552 (Tritanomaly), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0030500 (Yellow/white lesions of the macula), HP:0025158 (Hyperautofluorescent retinal lesion)

CaseHPOFreeText: The patient has been diagnosed with maculopathy and cone dystrophy.

CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Whole exome sequencing

CaseMethod2: Confirmation by Sanger sequencing

CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) variant in the heterozygous state.

ClinVar: 812328

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2521G>A (p.Glu841Lys) 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). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).

CaseAddInfo: The proband is a member of a family with an affected mother who was not genotyped.

CasePMIDs: N/A

Case#: Bowne_2011_Family_TCD-H_Patient_01, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was provisionally diagnosed with choroideremia prior to genotyping that excluded the presence of a variant in the CHM locus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

CaseMethod1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of the RPE65 locus

Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.

VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Shin_2015_Proband, male, age 26 years at time of report, national origin reported as Korean

CasePresentingHPOs: HP:0001956 (Truncal obesity), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0001631 (Atrial septal defect), HP:0001640 (Cardiomegaly), HP:0100598 (Pulmonary edema), HP:0012584 (Bilateral renal hypoplasia), HP:0004719 (Hyperechogenic kidneys), HP:0003774 (Stage 5 chronic kidney disease), HP:0000580 (Pigmentary retinopathy), HP:0000648 (Optic atrophy), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007754 (Macular dystrophy)

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome and has poor corticomedullary differentiation in the kidneys and optic disc atrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes.

CaseMethod1: Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping was performed using Sanger sequencing of the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS11, BBS12, BBS13, and BBS14 genes.

Variant: The patient harbors the NM_018190.4:c.103-1G>A and NM_018190.4:c.728G>A (p.Cys243Tyr) variants in the compound heterozygous state.

ClinVar ID: 166738

CAID: CA358045281

gnomAD: The NM_018190.4:c.103-1G>A variant was not found in gnomAD v2.1.1. The NM_018190.4:c.728G>A (p.Cys243Tyr) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0005515 (11/19944) in the East Asian population, with no homozygotes https://gnomad.broadinstitute.org/variant/4-122774232-C-T

VariantEvidence: NM_018190.4:c.103-1G>A is a canonical splice site variant in intron 2 adjacent to the boundary with exon 3 and does not have functional evidence of an impact on the protein product. NM_018190.4:c.728G>A (p.Cys243Tyr) is a missense variant in exon 8 that does not have functional evidence of an impact on the protein product, but has been previously reported in the homozygous state in a patient affected with retinitis pigmentosa (PMID: 23847139).

CaseAddInfo: Consanguinity is not present in the proband's family. He has a similarly affected brother who shares the same compound heterozygous genotype, and unaffected parents and sibling who each carry one BBS7 variant.

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_168, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.

CaseMethod1: NGS panel

CaseMethod2: N/A

CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1407+1G>A variant in the homozygous state.

ClinVar: 636053

gnomAD: The NM_000440.3(PDE6A):c.1407+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.0003267 (1/30606 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149277925-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1407+1G>A variant disrupts a canonical splice site in intron 10, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Khan_2015_Proband, female, age 12 years, family national origin described as Saudi

CasePresentingHPOs: Congenital nystagmus HP:0006934, Juvenile cataract HP:0001118, Reduced visual acuity HP:0007663, Posterior cortical cataract HP:0010924, Abnormal optic disc morphology (fibrosis over the optic disc) HP:0012795, Pigmentary retinopathy HP:0000580, Undetectable light-adapted electroretinogram HP:0030465, Abnormal dark-adapted electroretinogram (decreased amplitude) HP:0030469

CaseHPOFreeText: The proband's overall phenotype was summarized as "juvenile cataract in the setting of a congenital vitreo-retinal dystrophy notable for fibrosis over the disc and clumped pigmentation in the posterior pole". The authors comment that the phenotype should be described as; "early-onset vitreo-retinal degeneration (with early-onset cataract)" rather than as LCA, due to the presence of vitreous degenerative changes as well as the ERG being recordable in patients in the second decade of life and beyond.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes.

CaseMethod1: next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes

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 next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes. 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.359T>C (p.Ile120Thr) variant.

ClinVar: 191155

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00001562 (1 allele / 64034 total alleles) in the European (Finnish) population https://gnomad.broadinstitute.org/variant/2-232771004-A-G?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr) is a missense variant that has not been studied at the functional level.

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

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-30, female, age 30 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had hypopigmented clumped lesions in the posterior pole of both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.

ClinVarID: 191059

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3.

CaseAddInfo: The proband has an affected sibling who shares the same homozygous genotype.

CasePMIDs: N/A

Case#: Chang_2009_Family_CHRO102_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband and an affected family member were previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Affected and unaffected family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) and NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) variants in the compound heterozygous state.

ClinVar ID: 8769, 8772

gnomAD: The NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.2368G>A (p.Glu790Lys) acts in part as an exonic splicing variant that has been expressed in COS7 cells and triggers 40% of transcripts to skip exon 21 and undergo frameshift (Figure S5C). The remaining transcripts encode a missense variant that has been expressed in Sf9 cells and subjected to an enzymatic assay showing approximately 40% loss of activity (Figure 5). NM_006204.4(PDE6C):c.1805A>T (p.His602Leu) is a missense variant that has been expressed in Sf9 cells and subjected to an enzymatic assay showing approximately 90% loss of activity (Figure 5).

CaseAddInfo: The patient has an affected brother who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.

CasePMIDs: N/A

Case#: Thiadens_2009_Family_D_Proband_DII-1, female, age 12 years at onset and 37 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, described as severe), HP:0000639 (Nystagmus), HP:0031624 (Moderate myopia), HP:0000551 (Color vision defect, described as severe), HP:0030825 (Absent foveal reflex), HP:0030465 (Undetectable light-adapted electroretinogram)

CaseHPOFreeText: The proband and affected family member were previously diagnosed with complete achromatopsia. The proband had onset by age 12 years.

CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in this family appears to have been limited to phenotype analysis.

CaseMethod1: screening of the 22 exons and flanking regions of PDE6C (candidate gene) using Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Affected and unaffected family members were subjected to Sanger sequencing-based screening of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.633G>C (p.Glu211Asp) and NM_006204.4(PDE6C):c.1363A>G (p.Met455Val) variants in the compound heterozygous state.

ClinVar ID: 8768, 8767

gnomAD: Neither variant was found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.1363A>G (p.Met455Val) is a missense variant that does not have experimental evidence of a functional effect on the protein product. NM_006204.4(PDE6C):c.633G>C (p.Glu211Asp) is not a missense variant but rather a substitution of the last base pair of exon 2 that is predicted to disrupt the splice donor site.

CaseAddInfo: The patient's parents are apparently unaffected carriers. Her similarly affected sibling shares the same compound heterozygous genotype.

CasePMIDs: N/A

Case#: Weisschuh_2020_Patient_BVMD_75, male, age 61 years at diagnosis, age 66 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with best vitelliform macular dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.6 panel.

CaseMethod1: next generation sequencing-based RET.6 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.6 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.807+1G>C variant in the homozygous state.

ClinVar: 813048

gnomAD: The NM_001563.4(IMPG1):c.807+1G>C variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.807+1G>T is a canonical splice site variant in intron 7 that does not have evidence confirming an impact on the gene product.

CaseAddInfo: Segregation confirmation in family members is not available. The patient has a genotype that has been reported elsewhere in an apparently separate proband (PMID: 23993198, apparently of Italian national origin).

CasePMIDs: N/A

Case#: Suspitsin_2015_Proband_II.4, male, age 7 years at time of report, national origin reported as Russian

CasePresentingHPOs: HP:0004324 (Increased body weight), HP:0012743 (Abdominal obesity), HP:0000510 (Rod-cone dystrophy), HP:0100259 (Postaxial polydactyly), HP:0011220 (Prominent forehead), HP:0005280 (Depressed nasal bridge), HP:0000054 (Micropenis), HP:0001256 (Intellectual disability, mild), HP:5200120 (Abnormality in emotional social interactions)

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome and retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of exome sequencing, focused on the BBS1-BBS19 loci.

CaseMethod1: exome sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping consisted of exome sequencing, focused on the BBS1-BBS19 loci.

Variant: The patient harbors the NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) variant in the homozygous state.

ClinVar ID: 162088

gnomAD: The NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) variant was not found in gnomAD v2.1.1. However, the authors note that the healthy blood donors from the Russian population do carry the allele in the heterozygous state at a low frequency (0.07%).

VariantEvidence: NM_176824.3(BBS7):c.1967_1968delinsC (p.Leu656fs) is an out-of-frame indel in exon 18 of 18 and is not predicted to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband is a member of a non-consanguineous family, and has two unaffected carrier parents, an unaffected carrier sibling, and a similarly affected sister sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Nichols_1993_Proband, female, age and family origin not reported

CasePresentingHPOs: Subretinal deposits HP:0031528

CaseHPOFreeText: The proband has been diagnosed with butterfly-shaped pigment dystrophy of the fovea. All affected family members including the proband exhibited perifoveal yellow pigment deposits at the level of the RPE.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in this family appears to have been limited to the PRPH2 locus and did not include other candidates genes.

CaseMethod1: single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2

CaseMethod2: Sanger sequencing of PRPH2

CaseGenotypingMethod: Previous testing in this family appears to have been limited to the PRPH2 locus and did not include other candidates genes. Genotyping was performed by single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2, followed by Sanger sequencing of PRPH2 to identify the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) variant in the heterozygous state.

ClinVar ID: 13171

gnomAD: The NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.897_898del (p.Ser301fs) is a frameshift variant in exon 3 of 3 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 14% of the protein product.

CaseAddInfo: The proband has two affected sisters and an affected father who similarly carry the variant, as well as 6 unaffected family members who are negative for the variant.

CasePMIDs: N/A

Case#: Méjécase_2020_Family_6_Proband_6-1, sex not specified, age 8 years, family national origin described as from the United Arab Emirates

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband received a diagnosis of severe early onset retinal dystrophy. The fundus appearance was described as consistent with KCNJ13-retinopathy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was previously genotyped by a next-generation sequencing panel.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of KCNJ13

CaseGenotypingMethod: The proband was previously genotyped by a next-generation sequencing panel, followed by Sanger sequencing-based confirmation.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.431T>C (p.Leu144Pro) variant in the homozygous state.

ClinVar: 916717

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00001667 (1 / 59998) in the African / African-American population https://gnomad.broadinstitute.org/variant/chr2-232770932-A-G?dataset=gnomad_r4

VariantEvidence: NM_002242.4(KCNJ13):c.431T>C (p.Leu144Pro) is a missense variant that has no experimental evidence in this study

CaseAddInfo: The proband's family history includes a similarly affected 4-year-old sibling with the same homozygous genotype.

CasePMIDs: N/A

Case: Jacobson_1995_Family_1_Patient_III-5, male, country of origin United States (PMID:8981947), onset in 4th or early 5th decade of life

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The variant was inherited by the proband rather than acquired de novo.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0200056 (Macular scar), HP:0000608 (Macular degeneration), HP:0000603 (Central scotoma), HP:0025243 (Subretinal hemorrhage), HP:0000662 (Nyctalopia)

CaseHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring (secondary to subretinal hemorrhage) and degeneration.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: SSCP using PCR-amplified exon 5 from TIMP3, followed by Sanger sequencing of the exon 5 PCR product.

GenotypingMethod: PCR amplification of exon 5, followed by enzyme digestion with the Bbv1 restriction endonuclease.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Patients harbor the NM_000362.5(TIMP3):c.568G>T (p.Gly190Cys) missense variant.

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.

Patient G000986 has retinitis pigmentosa and is a compound heterozygote harboring two IMPG2 variants ().

Case#: Fishman_1998_Family_1_Patient_IV-6, male, age 18 at time of study, 6 years old at time of first examination, family origin Scottish and Irish, race reported as white

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000577 (Exotropia), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001105 (Retinal atrophy), HP:0000550 (Undetectable electroretinogram), HP:0000573 (Retinal hemorrhage)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting X-linked pattern of inheritance. Disease was reported to be relatively severe in this family.

CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0007957 (Corneal opacity), HP:0012795 (Abnormality of the optic disc)

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was not subjected to previous genetic testing outside of the RPGR locus.

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

CaseMethod2: N/A

CaseGenotypingMethod: The proband and his family members were subjected to Sanger sequencing of the PCR-amplified exons from the RPGR locus.

Variant: The proband harbors the NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) variant in the hemizygous state.

ClinVar: 9902

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

VariantEvidence: NM_001034853.2(RPGR):c.179G>T (p.Gly60Val) is a missense variant in exon 3 that has not been functionally characterized to confirm an impact on the gene product. It has been observed in multiple apparently unrelated families in this study (PMID: 9855162) and in one other study by the same group (PMID: 9399904). It may be a founder variant present within the population of the U.K.

CaseAddInfo: The proband is a member of Family 1, shown in Figure 1 from this study. Four other genotype-positive affected males are present in his extended family, as well as carrier females affected with patchy retinopathy (but no tapetal reflex).

CasePMIDs: N/A

Case#: van_Huet_2014_Patient_B-II:1, female, in childhood at time of onset, age 66 at the time of report, national origin reported as Iraqi Jewish

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.

CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

VariantEvidence: The NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant is a nonsense variant in exon 6 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 83% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has two affected sisters who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: L396P

Variant1ClinVarID:

Variant1CAID: CA355963499

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P496R

Variant1ClinVarID: 496861

Variant1CAID: CA2802275

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: A436P

Variant1ClinVarID:

Variant1CAID: CA355963897

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: G208D

Variant1ClinVarID: 554590

Variant1CAID: CA355961948

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: E276K

Variant1ClinVarID:

Variant1CAID: CA355962355

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H449N

Variant1ClinVarID: 350230

Variant1CAID: CA2802233

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H82P

Variant1ClinVarID: 195039

Variant1CAID: CA201510

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: E178K

Variant1ClinVarID: 2203495

Variant1CAID: CA355961709

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P385R

Variant1ClinVarID: 556024

Variant1CAID: CA355963438

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: H240R

Variant1ClinVarID: 947028

Variant1CAID: CA355962127

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1:

Variant1ClinVarID:

Variant1CAID: CA355963739

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: D315Y

Variant1ClinVarID:

Variant1CAID: CA355962740

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 2474, male, northern European origin, he was class valedictorian in high school and then a practicing attorney until his intellect deteriorated later in life.

DiseaseAssertion: MPS1-S, mild

FamilyInfo: Affected sister with MPS-1 who had a similar or slightly more severe clinical phenotype.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Fibroblasts has enabled detection of 0.041 ± 0.008 (n = 6) ng of IDUA protein of total cellular protein/mg (0.13% of normal mean). This gives a calculated specific activity and VmX, of 88 and 102 pmol/min/ng of IDUA toward the fluorogenic and heparin-derived disaccharide substrates, respectively, both of which are in the normal range.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.590-7G>A (678-7G>A)

Variant1ClinVarID: 222996

Variant1CAID: CA356990

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: OS of sibship 1, female, 8 years old (age at diagnosis), 8.8 years old (age at ERT enrollment), 5.4 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected male YS (YS of sibship 1)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0000365, HP:0001263, HP:0001260, HP:0002751 (Corneal opacity, dysostosis, joint contractures, mild hearing impairment, psychomotor delay, speech difficulty, kyphoscoliosis)

CaseHPOFreeText: Cardiac disease, lung function tests 50% of normal, organomegaly

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - symptoms present at T1 were stabilized or improved (organomegaly and hearing) at T2, except for worsening of kyphoscoliosis.

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: YS of sibship 4, male, 0.8 years old (age at diagnosis), 1.3 years old (age at ERT enrollment), 3.6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected male OS (OS of sibship 4)

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

CaseHPOFreeText: Cardiac disease, progression of respiratory symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - Had poor compliance (~60 %) with ERT, which may have impacted the symptom progression.

CaseBMT: N/A

Variant1: c.623G>A (p.G208D)

Variant1ClinVarID: 554590

Variant1CAID: CA355961948

Variant2: (p.P520R), Typo, no proline at this position

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected OS (OS of sibship 8)

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

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

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: YS of sibship 7, female, 3.3 years old (age at diagnosis), 3.4 years old (age at ERT enrollment), 5.6 years (duration of ERT)

DiseaseAssertion: MPS1-HS

FamilyInfo: Affected OS (OS of sibship 7)

CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0001270 (Corneal opacity, dysostosis, joint contractures, cognitive impairment, motor impairment)

CaseHPOFreeText: Cardiac disease, somatic impairment

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes - After 5 years of ERT, cardiac symptoms progressed but remained mild. Corneal clouding progressed as well. At the age of 5, motor development remained normal, and cognitive skills and musculoskeletal disease improved.

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: (L564fsx) No CDNA change provided.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-HS

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

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

CaseHPOFreeText: Cardiac disease, musculoskeletal symptoms

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

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

CaseBMT: N/A

Variant1: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P6, 8 months old (age at presentation), 2 years old (age at report), female, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Proband's parents were first cousins.

CasePresentingHPOs: Coarse facial features, recurrent respiratory tract infections, joint stiffness, upper airway obstructive symptoms, mild developmental delay, umbilical hernia (HP:0000256, HP:0002788, HP:0001387, HP:0002781, HP:0001263, HP:0001537)

CaseHPOFreeText: Widening of the wrist and a stunted, pectus carinatum

CaseNotHPOs: Visceromegaly (HP:0003271)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11919

Variant1CAID: CA220503

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

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P8, 10 years old (age at presentation), male, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Born to consanguineous parents

CasePresentingHPOs: Coarse facial features, mild developmental delay, short stature, pectus carinatum, genu valgum, corneal clouding (HP:0000256, HP:0001263, HP:0004322, HP:0000768, HP:0002857, HP:0007957)

CaseHPOFreeText: Difficulty walking since the age of 4 years. Widening of the wrist, underweight, soft abdomen.

CaseNotHPOs: Visceromegaly (HP:0003271)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID:

Variant1CAID: 11919

Variant2: CA220503

Variant2ClinVarID: c.1469T>C (p.L490P)

Variant2CAID: 11919

AdditionalVariants: CA220503

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P4, 16 months (age of presentation), male, Pakastani

DiseaseAssertion: MPS-I

FamilyInfo: Proband was born to a consanguineous family.

CasePresentingHPOs: Snoring, failure to thrive, developmental delay, coarse facial features, skeletal deformities, umbilical hernia (HP:0025267, HP:0001508, HP:0001263, HP:0000256, HP:0002652, HP:0001537)

CaseHPOFreeText: Copious nasal secretions, chest infections, underweight, and a liver span of 3 cm.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11919

Variant1CAID: CA220503

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

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: PKMPS1P5, 10 months old (age at presentation), 2 years old (age at report), female, Pakastani

DiseaseAssertion:MPS-I

FamilyInfo: Her parents were related

CasePresentingHPOs: Upper airway obstructive symptoms, stridor, developmental delay, coarse facial features, pneumonia, umbilical hernia, short neck, kyphosis (HP:0002781, HP:0010307, HP:0001263, HP:0000256, HP:0002090, HP:0001537, HP:0000470, HP:0002808)

CaseHPOFreeText: Copious nasal discharge, widening of the wrist, liver span was 3 cm.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.784delC (p.H262Tfs*55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

Variant2: c.784delC (p.H262Tfs*55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 17, 3 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249, HP:0100790)

CaseHPOFreeText: Cardiac disease

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.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 6, 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, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0000943, HP:0001249)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.362T>C (p.Leu121Pro)

Variant1ClinVarID: 1343382

Variant1CAID: CA355961174

Variant2: c.362T>C (p.Leu121Pro)

Variant2ClinVarID: 1343382

Variant2CAID: CA355961174

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 54, 8 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.3% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.568_581del (p.Asn190His)

Variant1ClinVarID: 3639714

Variant1CAID: CA2801994

Variant2: c.1469T>C (p.Leu490Pro)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 31, 6 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: Sibling of Patient 32

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: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3.0% (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 12, 7 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0001249)

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.532G>A (p.Glu178Lys)

Variant1ClinVarID: 2203495

Variant1CAID: CA355961709

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

Variant2ClinVarID: 2203495

Variant2CAID: CA355961709

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 23, 9 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Intellectual disability (HP:0001249)

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.1029C>A (p.Tyr353Ter)

Variant1ClinVarID: 222997

Variant1CAID: CA356984

Variant2: c.1029C>A (p.Tyr353Ter)

Variant2ClinVarID: 222997

Variant2CAID: CA356984

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 14, 5 years old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.543T>G (p.Asn181Lys)

Variant1ClinVarID: N/A

Variant1CAID: CA355961734

Variant2: c.543T>G (p.Asn181Lys)

Variant2ClinVarID: N/A

Variant2CAID: CA355961734

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 33 (Table 3)

DiseaseAssertion: Attenuated naïve MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 3 nmol/h/mg per DBS (dried blood spots) determined during NBS. 13.2 DBS protein concentration determined by Immuno-SRM (pmol/L).

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

Variant1: c.1577T>C (p.L526P)

Variant1ClinVarID: 567566

Variant1CAID: CA2802300

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

Variant2ClinVarID: 567566

Variant2CAID: CA2802300

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 29 (Table 3)

DiseaseAssertion: Severe naïve MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: <1 nmol/h/mg per DBS (dried blood spots) determined during NBS

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1524+1G>T

Variant2ClinVarID: 555169

Variant2CAID: CA355964830

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 32 (Table 3)

DiseaseAssertion: Moderate naïve MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 41 (Table 3)

DiseaseAssertion: Moderate MPS 1

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 77.5 DBS protein concentration determined by Immuno-SRM (pmol/L).

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: P4, Male, 13 years (diagnosed), 16.1 (report), 38 kg (weight), 146 cm (height), Algerian

DiseaseAssertion: Scheie Syndrome

FamilyInfo: Parents are consanguineous

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

CaseHPOFreeText: Cardiac Manifestations(Mitral Stenosis & Aortic Insufficiency)

CaseNotHPOs: HP:0001249, HP:0000238 (Mental Retardation, Hydrocephalus)

CaseNotHPOFreeText: Chronic Rhinorrhea

CaseEnzymeAssay: IDUA Enzyme activity 7 (% to the reference range mean)

CaseUrineGAGs: GAG quantitation 18 (fold change to the reference range mean according to age)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

Variant1: c.1598C>G (p.Pro533Arg)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: P12, Male, 2.6 years (diagnosed), 9.6 (report), Algerian

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Parents are not consanguineous

CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0001433, HP:0001387, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatosplenomegaly, Hernia(Ombelical), Hydrocephalus)

CaseHPOFreeText: Chronic Rhinorrhea

CaseNotHPOs: HP:0007957 (Corneal Opacity)

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

Variant1: c.1598C>G (p.Pro533Arg)

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2:c.1743C>G (p.Tyr581*)

Variant2ClinVarID: 550883

Variant2CAID: CA2802392

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 9, Turkish

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1598C>T (p.P533L)

Variant1ClinVarID: 429205

Variant1CAID: CA355965029

Variant2: c.1598C>T (p.P533L)

Variant2ClinVarID: 429205

Variant2CAID: CA355965029

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 6, Turkish

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.793-5C>A (homozygous)

Variant1ClinVarID: N/A

Variant1CAID: CA3250086379

Variant2: c.793-6C>G (homozygous)

Variant2ClinVarID: N/A

Variant2CAID: CA2739858898

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 31298590

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 6, Male, 1 year (diagnosed), 2 years (report), Djerba Island (Tunisian origin)

DiseaseAssertion: N/A

FamilyInfo: Parents are consanguineous between 2nd cousins

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Leukocyte IDUA activity 0.3% (% normal) ; determined in sonicated leukocyte pellets using the artificial substrate 4-methylumbellifery IDUA

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sequencing exons and intro-exon junctions; Phenol/chloroform procedure

Variant1: p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: p.P533R

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: p.A8A (c.24 A > C, p.A20A (c.60G > A); p.Q433Q (c.99T > G), IVS2-44 (c.300 44C > T); p.R105Q (c.314G > A); p.N181N (c.543 T > C), IVS5-45 (c.590-45G > C); IVS5-8 (c.590- 8C > T); p.A314A (c.942G > C); IVS7+48 (c.972+48A > G), IVS7-45 (c.973-45 G > C; p.A361 (Tc.1081G > A); p.T388T (c.116G > C); p.V454I (c.1360G > A); IVS9+36 (c.1402+36T > C), p.R489R (c.1467C > T), IVS12+72 (c.1727T > G), 3'UTR+44 (c.1962+44G > C).

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, Male, 2 years (diagnosed), 12 years (report), Sfax (Tunisian origin)

DiseaseAssertion: N/A

FamilyInfo: Parents are consanguineous between 3rd cousins

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Leukocyte IDUA activity 0.2% (% normal) ; determined in sonicated leukocyte pellets using the artificial substrate 4-methylumbellifery IDUA

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sequencing exons and intro-exon junctions; Phenol/chloroform procedure

Variant1: p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: p.P533R

Variant2ClinVarID: 11910

Variant2CAID: CA256112

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: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.523_534delTGGAACTTCGAG (p.Trp175_Glu178del)

Variant1ClinVarID: 2734635

Variant1CAID: CA645372297

Variant2: c.523_534delTGGAACTTCGAG (p.Trp175_Glu178del)

Variant2ClinVarID: 2734635

Variant2CAID: CA645372297

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-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.784_784delC (p.H262TfsTer55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

Variant2: c.784_784delC (p.H262TfsTer55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.13 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.158+1G>A

Variant1ClinVarID: 526835

Variant1CAID: CA355945713

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.17_24dupCCCGCGCC (p.Ala9ProfsTer102)

Variant1ClinVarID: N/A

Variant1CAID: CA645372294

Variant2: c.1871A>T (p.D624V)

Variant2ClinVarID: N/A

Variant2CAID: CA355965955

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.05 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.36_44delGCTCCTGGC (p.Leu13_Ala15del)

Variant1ClinVarID: 3720558

Variant1CAID: CA645372295

Variant2: c.1205G>A (W402X)

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 22280094

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Patient 6 (see Table 2), 33 weeks, 6 days (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.47 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 8 (see Table 2), 38 weeks (Gestational age)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Upper respiratory tract involvement

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.58 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 19 (see Table 2), 38 weeks (Gestational age)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Sibling of Patient 20 (see Table 2)

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 0.92 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 3 (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.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 24 (see Table 2), 40 weeks (Gestational age)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: Inguinal hernia (HP:0000023)

CaseNotHPOFreeText: Upper respiratory tract involvement

CaseEnzymeAssay: 1.05 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.1148G>A (p.R383H)

Variant2ClinVarID: 558189

Variant2CAID: CA:2802205

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 37516270

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Abnormal

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11917

Variant1CAID: CA256118

Variant2: c.1861C>T (p.R621X)

Variant2ClinVarID: 11917

Variant2CAID: CA256118

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A