Case#: Shen_2019_Patient_III-10, female, age 39 years at time of report, national origin reported as Chinese, ethnicity reported as Miao

CasePresentingHPOs: HP:0001513 (Obesity), HP:0000822 (Hypertension), HP:0000107 (Renal cyst), HP:0010442 (Polydactyly), HP:0000750 (Delayed speech and language development), HP:0000678 (Dental crowding), HP:0011342 (Mild global developmental delay), HP:0001156 (Brachydactyly), HP:0000470 (Short neck), HP:0005280 (Depressed nasal bridge), HP:0000140 (Abnormality of the menstrual cycle)

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

CaseNotHPOs: HP:0000134 (Female hypogonadism), HP:0002194 (Delayed gross motor development), HP:0000708 (Atypical behavior), HP:0000819 (Diabetes mellitus), HP:0000365 (Hearing impairment), HP:0000518 (Cataract), HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of exome sequencing.

CaseMethod1: exome sequencing

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping consisted of exome sequencing, followed by Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant in the homozygous state.

ClinVar ID: 216138

gnomAD: The NM_176824.3(BBS7):c.389_390del (p.Asn130fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_176824.3(BBS7):c.389_390del (p.Asn130fs) is an out-of-frame deletion variant in exon 5 of 18 that is predicted to trigger nonsense-mediated decay or at least truncation of the C-terminal 82% of the protein product.

CaseAddInfo: Consanguinity in the proband's family is suspected but has not been confirmed. She has two similarly affected cousins who share the same homozygous genotype. The carrier status of her unaffected parents and an unaffected sibling have been confirmed by genotyping.

CasePMIDs: N/A

Case#: Linder_2014_Proband_RP-106, female, age 20 years at time of onset / first visual complaints, age 73 year at time of report, family origin not reported

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Cataract HP:0000518, Attenuation of retinal blood vessels HP:0007843, Bone spicule pigmentation of the retina HP:0007737, Undetectable dark-adapted electroretinogram HP:0030474, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

CaseHPOFreeText: The proband has been diagnosed with sporadic retinitis pigmentosa. Phenotypes included pale papillae in fundus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants.

CaseMethod1: SSCP analysis of 14 PCR-amplified PRPF4 exons

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants. SSCP was performed on each of 14 PCR-amplified exons of PRPF4, followed by Sanger sequencing analysis.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant in the heterozygous state.

ClinVar ID: 967144

gnomAD: The NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant is found in gnomAD v4.1.0 at a frequency of 0.00004999 (3 / 60014, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/9-113283400-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) is a missense variant. When overexpressed in zebrafish, the variant fails to rescue the lethality of Prpf4 silencing, unlike overexpression of the wild-type gene (Figure 2). Co-immunoprecipitation experiments show that the variant localizes normally but disrupts interaction with PRPF3 (Figure 3) and blocks PRPF4 integration into snRNP complexes (Figure 4).

CaseAddInfo: The proband has two daughters at ages 52 and 54 years who harbor the variant but showed no retinal abnormalities in ophthalmological examinations.

CasePMIDs: N/A

Case#: Holmberg_Patient_7, female, age 4 at onset and age 9 at time of study, Finnish origin with some ancestors traced to Sweden

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 4, while mental decline, visual deterioration and abolished ERG were found at age 7. Ataxia and Seizures developed at age 8, while Loss of independent walking and Giant flash visual evoked potentials 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.

CaseNotHPOs: HP:0007082 (Dilated third ventricle)

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 a compound heterozygote harboring the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2564, 56543

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 The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC

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). NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is also a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_3, male, age 3 at onset and age 19 at time of death, 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 4, while mental decline, visual deterioration and abolished ERG were found at age 6. Giant flash visual evoked potentials were present at age 8, and ataxia at age 9. Seizures and Loss of independent walking occurred at age 10. 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.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#: Zou_2017_Patient_F2-II:1, male, age 3 at time of report, family national origin reported to be from China

CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)

CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.

CaseNotHPOs: HP:0007730 (Iris hypopigmentation)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing

CaseMethod2: N/A

CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.

Variant: The proband harbors the NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) variant in the hemizygous state.

CAID: CA411999243

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

VariantEvidence: NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) is a nonsense variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 77% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Stunkel_2018_Patient_5, female, age 45 at diagnosis with congenital night blindness, at least as early as age 4 at time of onset, 52 years old at time of report, ethnic origin not mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000552 (Tritanomaly), HP:0000539 (Abnormality of refraction), HP:0001133 (Constriction of peripheral visual field), HP:0007737 (Bone spicule pigmentation of the retina), HP:0008043 (Retinal arteriolar constriction), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram),

CaseHPOFreeText: Refractive error was minimal. Progression of nyctalopia was noticed at 44 years of age. Rod-based ERG was not detectable at age 52.

CaseNotHPOs: HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram), HP:0030617 (Abnormal OCT-measured foveal thickness)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Patient 5 was tested for known LCA-causing variants using an allele-specific method.

CaseMethod1: It is not clear whether Sanger sequencing was used to confirm the initial genotyping method.

CaseMethod2: N/A

CaseGenotypingMethod: Patient 5 was tested for known LCA-causing variants using an allele-specific method, leading to the detection of 2 variants in GUCY2D.

Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) and NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variants.

ClinVar: 98563, 854601

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 The NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant has a maximum allele frequency of 0.00004007 in gnomAD version 2.1.1 (in the African / African-American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917215-C-T

VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.2281C>T (p.p.Arg761Trp) variant is limited to computational prediction. 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: The possibility of consanguinity and variant phase have not been reported in detail.

CasePMIDs: N/A

Case: Tabata_1998_Family_Ch_patient_1, male, 52 years of age at onset of visual symptoms, country of origin Japan

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The proband passed on the variant to his son and likely inherited it from his affected mother (who was not genotyped).

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss), HP:0000603 (Central scotoma)

CaseHPOFreeText: Onset of decreased central vision was seen in the 6th decade of life (both eyes between the ages of 52 and 57).

CaseNOTHPOs: HP:0007994 (Peripheral visual field loss), HP:0000512 (Abnormal electroretinogram)

CaseNOTHPOFreeText: Although central vision was progressively lost, peripheral fundi have remained uninvolved and the individual has continued to walk unguided into the 8th decade of his life.

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant introduces an extra base within a splice acceptor site within intron 4, two bases upstream of exon 5.

Case#: Littink_2009_Family_Proband_II-1, male, onset in early childhood, age 12 years at time of report, family ancestry reported as Dutch

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000551 (Color vision defect)

CaseHPOFreeText: The proband and his sibling have a diagnosis of cone-rod dysfunction, including color vision described as severely abnormal and electroretinogram responses that showed absent cone a-wave but normal-to-subnormal rod function.

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13.

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of CABP4

CaseGenotypingMethod: Genotyping began with homozygosity mapping of the sibling and his affected sister that identified a shared region of homozygosity on chromosome 13, followed by Sanger sequencing of PCR products from the CABP4 gene.

Variant: The individual harbors the NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) variant in the homozygous state.

ClinVar ID: 190959

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0001418 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67457677-C-T?dataset=gnomad_r4

VariantEvidence: NM_145200.5(CABP4):c.646C>T (p.Arg216Ter) is a nonsense variant within exon 4 of 6 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband's family includes a similarly affected sister harboring the variant in the homozygous state, and unaffected parents who each carry the variant in the heterozygous state. Consanguinity has not been commented upon.

CasePMIDs: N/A

Case#: van_Huet_2014_Patient_A-II:1, female, age 8 years at the time of onset, age 59 at the time of report, national origin reported as Dutch

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0000545 (Myopia), HP:0000550 (Undetectable electroretinogram), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary 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)

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.887+430_908+274del variant in the homozygous state.

ClinVar: 3547

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

VariantEvidence: The NM_016247.4(IMPG2):c.887+430_908+274del variant is a deletion of exon 9 that is predicted to lead to in-frame removal of a region encoding 7 amino acids. When expressed exogenously in COS-1 cells, this results in retention of the protein product in the endoplasmic reticulum and failure to properly localize to the plasma membrane (PMID: 20673862, Figure 4).

CaseAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous. The proband has two affected siblings who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

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

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

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

CaseNotHPOs:

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

CaseMethod1: NGS panel

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

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

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

CAID: Variant 1) CA144657; Variant 2) CA356375011

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

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

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

Case#: Qin_2005_Patient_7, gender not reported, age 1 year at report, national origin reported as Japanese

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density), HP:0008052 (Retinal fold), HP:0000541 (Retinal detachment)

CaseHPOFreeText: The patient has been diagnosed with FEVR. Retinal folds and later complete retinal detachment were present in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.

CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.

Variant: The patient harbors the NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variants in the compound heterozygous state.

ClinVar: 2137179

CAID: CA224268235

gnomAD: The NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) variant was found in gnomAD v2.1.1 at a frequency of 0.00001759 (2/113686) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68170970-C-T?dataset=gnomad_r2_1

VariantEvidence: NM_002335.4(LRP5):c.1604C>T (p.Thr535Met) and NM_002335.4(LRP5):c.1850T>G (p.Phe617Cys) are missense variants in exons 8 and 9, respectively, out of 23. Neither has evidence of an impact on the gene product.

CaseAddInfo: The proband's parents are carriers for p.Phe617Cys (maternal) and p.Thr535Met (paternal). The father was apparently unaffected in terms of retinal change and reduced bone mass. The mother was subclinically affected unilaterally with localized retinal avascularization with tortuosity of the retinal vessels and reduced bone density.

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FV1, male, 10 years of age at time of study, ethnicity not specified

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0000510 (Rod-cone dystrophy), HP:0000512 (Abnormal electroretinogram), HP:0004322 (Short stature), HP:0001363 (Craniosynostosis), HP:0030799 (Scaphocephaly), HP:0001999 (Abnormal facial shape), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000365 (Hearing impairment), HP:0003774 (Stage 5 chronic kidney disease), HP:0000107 (Renal cyst), HP:0004719 (Hyperechogenic kidneys), HP:0005565 (Reduced renal corticomedullary differentiation), HP:0001510 (Growth delay)

CaseHPOFreeText: This proband was diagnosed with Mainzer-Saldino syndrome.

CaseNotHPOs: HP:0000639 (Nystagmus)

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.3916dup (p.Ala1306fs) variants in IFT140.

ClinVar: 31683, 31684

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.3916dup (p.Ala1306fs) variant is present in gnomAD at a frequency of 0.0001210 in the African / African-American population (3/24790, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1570005-G-GC

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). NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) is a frameshift variant that introduces a premature stop codon in exon 28/31 and is predicted to trigger NMD or at least to truncate ~11% of the protein product.

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

CasePMIDs: N/A

Case#: Perrault_2012_Patient_FIV3, male, 17 years of age at time of study, Saudi Arabian national origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0000729 (Autistic behavior), HP:0001250 (Seizure), HP:0008499 (High hypermetropia), HP:0001123 (Visual field defect), HP:0007663 (Reduced visual acuity), HP:0000550 (Undetectable electroretinogram), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand), HP:0000556 (Retinal dystrophy)

CaseHPOFreeText: Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient. IFT140 protein localization along the ciliary axoneme was unaffected, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.

CaseNotHPOs: HP:0004322 (Short stature), HP:0000765 (Abnormal thorax morphology), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology), HP:0003272 (Abnormal hip bone 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: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T

VariantEvidence: Exogenous expression of the FLAG-tagged p.Glu664Lys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a relatively severe defect in localization to the basal body in most cells, relative to other suspected pathogenic missense variants and the wild-type control (Figure 3A).

CaseAddInfo: The proband's parents are reportedly consanguineous (first cousins).

CasePMIDs: N/A

Case#: Perrault_2000_Family_3_Proband, Female, age unknown, family origin in Tunisia with Jewish Sefardi 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:c.389del (p.Pro130LeufsTer36) variant.

ClinVar: 98602

gnomAD: The variant exhibits a maximum allele frequency of 0.00008370 in gnomAD version 2.1.1 (in the Latino / Admixed American population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7906751-AC-A

VariantEvidence: The NM_000180.4:c.389del (p.Pro130LeufsTer36) variant is predicted to trigger nonsense mediated decay or to disrupt ~88% of the protein product by frameshift.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

Case#: Family_9073_Proband_III-1, 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:c.757C>T (p.Gln253Ter) variant in the hemizygous state.

CAID: CA415307744

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

VariantEvidence: NM_020061.6:c.757C>T (p.Gln253Ter) is a nonsense variant in exon 5 of 6 that is predicted to undergo nonsense-mediated decay.

CaseAddInfo: The proband was seen at a medical center in Guangzhou. A maternal uncle is similarly affected but ungenotyped.

CasePMIDs: N/A

Case: Felbor_1997_Family_1_patient_III-4, gender not specified, country of origin Finland, onset not specified

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: N/A

CaseHPOFreeText: While phenotypes were not described for the specific proband, the affected family members exhibit early onset of visual loss between the second and fourth decade of life, with the first sign in young family members being uneven or absent pigmentation in the extreme fundus periphery. Affected individuals experience progressive vision loss, iris atrophy, and glaucoma in some cases.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a disease-specific mobility shift in exon 5. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene in comparison to a control individual.

GenotypingMethod: Enzymatic digestion of TIMP3 exon 5 PCR products with the HaeIII restriction endonuclease.

PreviouslyPublished: This highly consanguineous family was previously published in PMID:7148944 and PMID:2387082. It was proposed to show an autosomal recessive pattern of inheritance (not previously observed for Sorsby fundus dystrophy). The family has been genotyped for the first time in this study, revealing segregation of disease phenotypes with a heterozygous variant in TIMP3, with autosomal dominant inheritance.

SupplementalData: N/A

Variant: Proband harbors the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.

ClinVar: 12679

gnomAD: Variant is absent from gnomAD.

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

Case#: Narumi_2010_patient_4, male, age 7 years at report, national origin listed as Japanese

CasePresentingHPOs: HP:0000555 (Leukocoria, bilateral), HP:0000541 (Retinal detachment), HP:0007968 (Remnants of the hyaloid vascular system), HP:0000529 (Progressive visual loss), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0002757 (Recurrent fractures), HP:0000938 (Osteopenia), HP:0000926 (Platyspondyly), HP:0000774 (Narrow chest), HP:0000883 (Thin ribs), HP:0003100 (Slender long bone), HP:0004322 (Short stature), HP:0004349 (Reduced bone mineral density)

CaseHPOFreeText: The patient has been diagnosed with osteoporosis-pseudoglioma syndrome. Minor breathing problems were observed at birth.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping appears to have been limited to the LRP5 locus and the surrounding genomic region.

CaseMethod1: Oligonucleotide tiling microarray analyses in the 600-kb region around LRP5.

CaseMethod2: Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus

CaseGenotypingMethod: Genotyping appears to have been limited to oligonucleotide tiling microarray analyses in the 600-kb region around LRP5, and Sanger sequencing of 23 PCR-amplified exons and flanking regions of the LRP5 locus.

Variant: The patient harbors the NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants in the compound heterozygous state.

ClinVar: 40291, 40292

gnomAD: The NM_002335.4(LRP5):c.1584+1G>A and NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variants were not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1584+1G>A is a canonical splice site variant that triggers the inclusion of 63 aberrant base pairs between exons 7 and 8 (Figure 3A). NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del is a 7.2-kb microdeletion that removes the final two exons of LRP5, disrupting the C-terminal 7% of the protein product.

CaseAddInfo: The patient has 2 apparently unaffected parents, one of whom carries the NM_002335.4(LRP5):c.1584+1G>A variant (mother) and one of whom carries the NC_000011.8:g.(67967534_67967551)_(67974756_67974774)del variant (father). Both parents and a carrier sister had significantly decreased bone mineral density, and the father had multiple reported long bone fractures.

CasePMIDs: N/A

Case#: Jiang_2015_Family_010153_Patient_III:1, female, age 37 at time of report, national origin listed as Chinese

CasePresentingHPOs: HP:0003621 (Juvenile onset), HP:0007663 (Reduced visual acuity), HP:0000639 (Nystagmus), HP:0030329 (Retinal thinning), HP:0011516 (Achromatopsia), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia)

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 and her 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>C (p.Arg838Pro) variant in the heterozygous state.

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) 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).

CaseAddInfo: The proband is a member of a family with several other affected family members who carry the variant.

CasePMIDs: N/A

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

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

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

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

CaseMethod1: SSCP

CaseMethod2: Sequencing

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

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

ClinVar: 1) 13010; 2) N/A

CAID: 1) CA034664; 2) CA7066374

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

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

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

CasePMIDs: 14281981

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

Case#: Holmquist_2021_Proband, onset before age 6 years, male, family national origin from Sweden

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 PCR / RFLP-based analysis of OPN1LW and OPN1MW locus structure, real-time PCR-based analysis of OPN1LW and OPN1MW copy number, and Sanger sequencing of long-range PCR products from exon 3 of OPN1LW and OPN1MW.

CaseMethod1: RFLP- and RT-PCR-based analyses of OPN1LW and OPN1MW structure and copy number

CaseMethod2: long-range PCR and Sanger sequencing of OPN1LW and OPN1MW

CaseGenotypingMethod: Genotyping of the proband was performed by RFLP- and RT-PCR-based analyses of OPN1LW and OPN1MW structure and copy number, followed by long-range PCR and Sanger sequencing of OPN1LW and OPN1MW.

Variant: The individual harbors the NM_020061.6(OPN1LW):c.511_513delinsATT (p.Val171Ile) and NM_020061.6(OPN1LW):c.532A>G (p.Ile178Val) variants in the hemizygous state.

ClinVarID / CAID: CA2695237719 / 403267

gnomAD: The NM_020061.6(OPN1LW):c.511_513delinsATT (p.Val171Ile) variant was not found in gnomAD v4.1.0. The NM_020061.6(OPN1LW):c.532A>G (p.Ile178Val) variant is found in gnomAD v4.1.0 at a frequency of 0.04886 in the African / African American population, with 862 total homozygotes.

VariantEvidence: NM_020061.6(OPN1LW):c.511_513delinsATT (p.Val171Ile) and NM_020061.6(OPN1LW):c.532A>G (p.Ile178Val) are missense variants in exon 3 that make up the "LIAVA" genotype that has been previously reported in the context of this disease (PMID: 22732407) but individually are not known to be disease-causing.

CaseAddInfo: The proband has a similarly affected brother who shares the same genotype, and an unaffected brother who does not harbor the variants.

CasePMIDs: PMID: 27339364

Case#: Kim_1995_Proband_III-14, female, age 59 years at time of report, family national origin reported as English

CasePresentingHPOs: Subretinal deposits HP:0031528, Pigmentary retinopathy HP:0000580, Disciform macular scar HP:0025094, Dark choroid HP:0025148, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Anomalous trichromacy HP:0011519, Reduced visual acuity HP:0007663, Decreased Arden ratio of electrooculogram HP:0008179

CaseHPOFreeText: The proband has been diagnosed with pattern dystrophy of the retina/macula. 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 is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes.

CaseMethod1: single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2 (described in PMID: 8004111)

CaseMethod2: Sanger sequencing of PRPH2 (described in PMID: 8004111)

CaseGenotypingMethod: Previous testing in this family is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes. Genotyping methods are previously described in PMID: 8004111 and included SSCP analysis of PCR products from the 3 exons of PRPH2 and Sanger sequencing of PRPH2

Variant: The proband harbors the NM_000322.5(PRPH2):c.418_421dup (p.Tyr141fs) variant in the heterozygous state.

ClinVar ID: 13174

gnomAD: The NM_000322.5(PRPH2):c.418_421dup (p.Tyr141fs) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.418_421dup (p.Tyr141fs) is a frameshift variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal 60% of the protein product.

CaseAddInfo: The proband has five affected extended family members who similarly carry the variant, as well as 7 unaffected family members who are negative for the variant.

CasePMIDs: PMID: 8004111

Case#: Yzer_2006_Patient_21557, male, age 4 months at diagnosis, Dutch or Belgian family origin

CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000618 (Blindness), HP:0030553 (Visual acuity no light perception), HP:0000563 (Keratoconus), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0020049 (Exodeviation), HP:0000518 (Cataract), HP:0000639 (Nystagmus),

CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Bilateral cataracts were dense and prevented fundoscopy.

CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia)

CaseNotHPOFreeText: N/A

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 note reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.

CasePMIDs: N/A

Case#: Haider_2000_Proband_3, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) variant in the homozygous state.

ClinVarID: 5529

gnomAD: The variant is not found in gnomAD version 4.1.0 at a frequency of 0.0001124 in the South Asian population (10 alleles / 88,960 total alleles, with no homozygotes) https://gnomad.broadinstitute.org/variant/chr15-71811590-C-T?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Khan_2015_Family_PKRP133_Patient_21, male, age not specified, family of Pakistani origin from the Punjab province

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor), HP:0000608 (Macular degeneration), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: The proband and his family members have been diagnosed with retinitis pigmentosa, with family history consistent with retinal dystrophy with early / congenital onset. Loss of visual acuity progressed to only counting fingers.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis was performed with several hundred markers, in combination with haplotype analysis of the patient and family members to map the causal variant to chromsome 5q33-35.

CaseMethod1: Whole-genome linkage analysis and haplotype analysis

CaseMethod2: Whole-exome sequencing of one family member followed by Sanger sequencing of others, including the patient.

CaseGenotypingMethod: Genome-wide linkage analysis was performed with several hundred markers, in combination with haplotype analysis of the patient and family members to map the causal variant to chromsome 5q33-35. This was followed by whole-exome sequencing of one family member and Sanger sequencing of the PDE6A locus in the patient.

Variant: The proband harbors the NM_000440.3:c.2028-1G>A variant in the homozygous state.

CAID: CA361692783

gnomAD: The NM_000440.3:c.2028-1G>A variant is not found in gnomAD v2.1.1.

VariantEvidence: The NM_000440.3:c.2028-1G>A variant disrupts a canonical splice site in intron 17, but does not have experimental confirmation of exon 17 skipping or frameshift.

CaseAddInfo: The proband is part of a large family known to have other affected family members and to include consanguineous unions.

CasePMIDs: N/A

Case#: Weisschuh_2018_Patient_3, sex unreported, age 17 years at time of report, likely from Europe or of European descent

CasePresentingHPOs: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0000639 (Nystagmus)

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.1579C>T (p.Arg527Ter) variant in the homozygous state.

ClinVar ID: 487692

gnomAD: The NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.0002603 (9/34574) in the Latino / Admixed-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/10-95399923-C-T

VariantEvidence: NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) is a nonsense variant in exon 12 of 22 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 39% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

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

DiseaseAssertion: Scheie Syndrome

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

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

CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Insufficiency)

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

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: GAG quantitation 44 (fold change to the reference range mean according to age)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: Scheie Syndrome

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

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

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

CaseNotHPOs: HP:0001249, (Mental Retardation)

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: GAG quantitation 22 (fold change to the reference range mean according to age)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: Scheie Syndrome

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

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

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

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

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Direct DNA Fragments Sequencing

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

Variant2ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Taiwanese newborn

DiseaseAssertion: MPS-I

FamilyInfo: Probands mother and father had genetic testing conducted.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 2432701

Variant1CAID: CA2801882

Variant2: c.99T>G (H33Q)

Variant2ClinVarID: 92651

Variant2CAID: CA145894

AdditionalVariants: N/A

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

PreviouslyPublished Yes, PMID:24053568

Case#: 0.1% residual activity at 37 °C

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 1.8% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 3233261

Variant1CAID: CA355962355

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

ClinVarID: 3233261

Variant2CAID: CA355962355

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.3% residual activity at 37 °C

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11910

Variant1CAID: CA256112

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

ClinVarID: 11910

Variant2CAID: CA256112

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.6% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: N/A

ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 1.2% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 3233261

Variant1CAID: CA355962355

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

ClinVarID: 3233261

Variant2CAID: CA355962355

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: 0.9% residual activity at 37 °C

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11917

Variant1CAID: CA256118

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

ClinVarID: 550382

Variant2CAID: CA2802114

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.6 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.713T>G (p.L238R)

Variant1ClinVarID: 2581619

Variant1CAID: CA2802064

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

Variant2ClinVarID: 1076379

Variant2CAID: CA2499217013

AdditionalVariants: N/A

ParentalGenotype: Father - c.882dupC (In article - c.883dupC). Mother - c.713T>G. The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

Variant2: c.1402+1G>T

Variant2ClinVarID: 1323099

Variant2CAID: CA355964387

AdditionalVariants: N/A

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

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.536C>G (p.T179R)

Variant1ClinVarID: 556358

Variant1CAID: CA355961718

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

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

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.4 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.46_57del12 (p.Ser16_Ala19del)

Variant1ClinVarID: 92643

Variant1CAID: CA220509

Variant2: c.792+1G>C

Variant2ClinVarID: N/A

Variant2CAID: CA355962280

AdditionalVariants: N/A

ParentalGenotype: Father - c.46-57del12, Mother - c.792+1G>C. The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 4, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Airway obstruction (HP:0001263, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

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

Variant1ClinVarID: N/A

Variant1CAID: CA2669476183

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 8, male, Han origin, 6 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

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

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1037T>G (p.L346R)

Variant1ClinVarID: 11927

Variant1CAID: CA256128

Variant2: c.1402+2T>G

Variant2ClinVarID: 553131

Variant2CAID: CA355964392

AdditionalVariants: N/A

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

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.532G>A (p.E178K)

Variant1ClinVarID: 2203495

Variant1CAID: 355961709

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay (HP:0001263)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.4 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

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

CaseERT: N/A

CaseBMT: N/A

Variant1: c.349delT (p.Tyr117ThrfsTer16)

Variant1ClinVarID: 1451219

Variant1CAID: CA2573137553

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

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

AdditionalVariants: N/A

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

PreviouslyPublished N/A

PMID: 21624210

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

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

DiseaseAssertion: MPS1

FamilyInfo: Proband's mother was pregnant and her genomic DNA was extracted from cultured amniocytes, her fetus did not acquire the same pathogenic gene as the proband and was a normal fetus.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Proband was diagnosed using enzymatic detection. IDUA enzyme activity in the mother's amniotic fluid cells in the 2nd pregnancy was 9.0 nmol/(h·mg protein).

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.713T>G (p.Leu238Arg)

Variant1ClinVarID: 2581619

Variant1CAID: CA2802064

Variant2: c.882dupC, in the article this is written as c.883insC (old nomenclature). Various variants from Wang articles have nomenclature errors that are 1 base pair off from the described variant.

Variant2ClinVarID: 1076379

Variant2CAID: CA2499217013

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: R363C

Variant1ClinVarID: 557205

Variant1CAID: CA2802184

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: L490P

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: X654C

Variant1ClinVarID: Not sure how to look up in CAR

Variant1CAID: Not sure how to look up in CAR

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: A591T

Variant1ClinVarID: 92635

Variant1CAID: CA145876

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: R162I

Variant1ClinVarID:

Variant1CAID: CA355961607

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: R89Q

Variant1ClinVarID: 11922

Variant1CAID: CA256124

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: G84R

Variant1ClinVarID:

Variant1CAID: CA355946488

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: M504T

Variant1ClinVarID:

Variant1CAID: CA355964770

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: G197D

Variant1ClinVarID: 554670

Variant1CAID: CA91167598

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P496L

Variant1ClinVarID: 551675

Variant1CAID: CA91170412

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: G265R

Variant1ClinVarID: 638074

Variant1CAID: CA2802098

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: R489P

Variant1ClinVarID: 1518214

Variant1CAID: CA355964650

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: R105Q

Variant1ClinVarID: 92641

Variant1CAID: CA145881

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: D349Y

Variant1ClinVarID: 638075

Variant1CAID: CA355963146

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: A160D

Variant1ClinVarID:

Variant1CAID: CA355961593

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: A327P

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

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: A319V

Variant1ClinVarID: 1683230

Variant1CAID: CA2802126

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: MPS 1 patient

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

Variant2: c.1727+2T>G

Variant2ClinVarID: 4539819

Variant2CAID: CA355965300

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: MPS 1 patient

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1139A>G (p.Q380R)

Variant1ClinVarID: 550779

Variant1CAID: CA2802202

Variant2: c.1139A>G (p.Q380R)

Variant2ClinVarID: 550779

Variant2CAID: CA2802202

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family D proband, female, 2 months and 5 days old (age of diagnosis), 14 months old (age of onset), 10 years old (age at report), Tunisia.

DiseaseAssertion: MPS1-H

FamilyInfo: No affected family members (See Fig. 1), parents were 1st degree relatives (first cousins) (See Table 1).

CasePresentingHPOs: HP:0002094, HP:0001605, HP:0001999, HP:0004322 (Dyspnea, laryngeal paralysis, abnormal facial shape, short stature)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity (0.1 nmol/h/mg) (usual values: 1-5).

CaseUrineGAGs: glycosaminoglycans (97 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1743C>G (p.Y581X)

Variant1ClinVarID: 550883

Variant1CAID: N/A

Variant2: c.1743C>G (p.Y581X)

Variant2ClinVarID: 550883

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family A proband, male, 11 years old (diagnosis), Tunisia.

DiseaseAssertion: MPS1-S

FamilyInfo: No other affected family members (See Fig. 1). Parents are 3rd degree relatives (See Table 1).

CasePresentingHPOs: HP:0001263, HP:0000280, HP:0000238, HP:0001433, HP:0000158, HP:0012471, HP:0000574, HP:0000520, HP:0000365, HP:0004322 (Global developmental delay, course facial features, hydrocephalus, hepatosplenomegaly, macroglossia, thick lips, bushy eyebrows, exophthalmos, hearing loss, short stature)

CaseHPOFreeText: Noisy breathing

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity (0.1 nmol/h/mg) (usual values: 1-5)

CaseUrineGAGs: glycosaminoglycans (136 mg/g of creatinine) (usual values: 6-23), abnormal electrophoresis profile (dermatan sulfate and heparan sulfate).

CaseERT: No

CaseBMT: No

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#: Family C proband, male, 1 year and 8 months old (age of diagnosis), 2 years old (age of death), Tunisia.

DiseaseAssertion: MPS1-H

FamilyInfo: No affected family members (See Fig. 1). Parents were 1st degree relatives (First child of first cousins) (See Table 1).

CasePresentingHPOs: HP:0001263, HP:0000280, HP:0001131, HP:0001513 (Global developmental delay, course facial features, corneal dystrophy, obesity)

CaseHPOFreeText: Abnormal flexibility of joints

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: DUA activity (0.1 nmol/h/mg) (usual values: 1-5)

CaseUrineGAGs: Glycosaminoglycans (116 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.

CaseERT: No

CaseBMT: No

Variant1: c.1587_1588dup (p.Leu530Argfs*31) (Information pulled from separate article PMID: 21639919) Article had written p.L530fs (1587_1588 insGC) (See article 12). However, upon looking at the chromatogram (Fig. 2), it was noted that there was an error in the nomenclature. A duplication had occurred rather than an insertion.

Variant1ClinVarID: 2203498

Variant1CAID: CA2580616050

Variant2: c.1587_1588dup (p.Leu530Argfs*31) (Information pulled from separate article PMID: 21639919)

Variant2ClinVarID: 2203498

Variant2CAID: CA2580616050

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 31, Italy

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1166_1171dup

Variant1ClinVarID: N/A

Variant1CAID: CA2586965963

Variant2: c.1166_1171dup

Variant2ClinVarID: N/A

Variant2CAID: CA2586965963

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 70, Spain

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.1189+4A>G

Variant2ClinVarID: N/A

Variant2CAID: CA2586965964

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 16, Italy

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1269C>A (p.S423R)

Variant1ClinVarID: 856833

Variant1CAID: CA91169964

Variant2: c.562T>C (p.F188L)

Variant2ClinVarID: N/A

Variant2CAID: CA355961777

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 64, Spain

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1189+4A>G

Variant1ClinVarID: N/A

Variant1CAID: CA2586965964

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

Variant2ClinVarID: 11917

Variant2CAID: CA256118

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 34, Italy

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.307A>C (p.T103P)

Variant1ClinVarID: N/A

Variant1CAID: CA355960996

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 22, Italy

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

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

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12, Italy

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1044C>G (p.N348K)

Variant1ClinVarID: 557870

Variant1CAID: CA2802172

Variant2: c.1727+5G>C

Variant2ClinVarID: N/A

Variant2CAID: CA2586965991

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 28, Italy

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.380_382del (p.Leu127del)

Variant1ClinVarID: N/A

Variant1CAID: CA2586973517

Variant2: c.380_382del (p.Leu127del)

Variant2ClinVarID: N/A

Variant2CAID: CA2586973517

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 15, Italy

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1333_1335del (p.Asp445del)

Variant2ClinVarID: 840115

Variant2CAID: CA916082626

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 102, Greece

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.250G>C (p.G84R)

Variant1ClinVarID: 3906899

Variant1CAID: CA355946488

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

Variant2ClinVarID: 3233261

Variant2CAID: CA355962355

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 17, Italy

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 11909

Variant1CAID: CA204563

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

Variant2ClinVarID: 496861

Variant2CAID: CA2802275

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 86, Turkey, patient belong to the same geographical region as patients 90, 92, and 98

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.494-1G>A

Variant1ClinVarID: 557942

Variant1CAID: CA355961634

Variant2: c.494-1G>A

Variant2ClinVarID: 557942

Variant2CAID: CA355961634

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 38, Poland

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

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

Variant1ClinVarID: 167190

Variant1CAID: CA234128

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

Variant2ClinVarID: 11908

Variant2CAID: CA220498

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2, 12 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.3 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.401G>T (p.G134V)

Variant1ClinVarID: N/A

Variant1CAID: CA355961317

Variant2: c.401G>T (p.G134V)

Variant2ClinVarID: N/A

Variant2CAID: CA355961317

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, 9 years old, Iranian

DiseaseAssertion: MPSI-H (Severe)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.12 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.469T>C (p.S157P)

Variant1ClinVarID: N/A

Variant1CAID: CA355961573

Variant2: c.469T>C (p.S157P)

Variant2ClinVarID: N/A

Variant2CAID: CA355961573

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Severe MPS1 patients, 2 individuals with this genotype

DiseaseAssertion: Severe MPS I

FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"

CasePresentingHPOs:

CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: n/a

PreviouslyPublished: possible since this is a multinational registry

Variant: c.1403‐1G > T/Q400X

ClinVar: 1683229

CAID: CA355963534

SupplementalData: n/a

Case#: Patient 15, female, 9 years (age at presentation).

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0001537)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.971A>G (p.K324R)

Variant1ClinVarID: N/A

Variant1CAID: CA355962881

Variant2: c.971A>G (p.K324R)

Variant2ClinVarID: N/A

Variant2CAID: CA355962881

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 19, female, 8 months (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomegaly, cardiomyopathy, dystosis multiplex, hepatomegaly, joint stiffness, Mongolian blue spots, splenomegaly, recurrent respiratory infections, umbilical hernia, global developmental delay (HP:0007957, HP:0000256, HP:0001640, HP:0001638, HP:0000943, HP:0002240, HP:0001387, HP:0011369, HP:0001744, HP:0002205, HP:0001537, HP:0001263)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1402+1G>A

Variant1ClinVarID: 555490

Variant1CAID: CA355964379

Variant2: c.1402+1G>A

Variant2ClinVarID: 555490

Variant2CAID: CA355964379

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, male, 2 years (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomegaly, dystosis multiplex, global developmental delay, hepatomegaly, joint stiffness, recurrent respiratory infections, sleep disturbances (HP:0007957, HP:0000256, HP:0001640, HP:0000943, HP:0001263, HP:0002240, HP:0001387, HP:0002205, HP:0002360)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.540G>A (p.W180X)

Variant1ClinVarID: 1321357

Variant1CAID: CA355961724

Variant2: c.540G>A (p.W180X)

Variant2ClinVarID: 1321357

Variant2CAID: CA355961724

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, male, 1 year and 6 months (age at presentation)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint contractures, extensive Mongolian spots (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0100790, HP:0011369)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>A (p.A75T)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>A (p.A75T)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 21, male, 4 years (age at presentation).

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, motor delay, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0001270, HP:0001744)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.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#: Proband of family A, which is an inbred Pakistani family, 16 months old (age at report)

DiseaseAssertion: MPS I - Severe

FamilyInfo: Family A is an inbred Pakistani family

CasePresentingHPOs: Asthma, sleep apnea, joint contractures, kyphosis, coarse facial features, hepatosplenomegaly, inguinal hernia, thick eyebrow, large tongue, thick lips (HP:0002099, HP:0010535, HP:0100790, HP:0002808, HP:0000256, HP:0001433, HP:0000023, HP:0000574, HP:0000158, HP:0000219)

CaseHPOFreeText: Ear/nose/throat infections, aggressive (behavior?), rough skin

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A