Case#: 31

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 17/25%, Mild Phenotype, inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3(F8):c.6506G>A (p.Arg2169His)

ClinVar: 10315 https://www.ncbi.nlm.nih.gov/clinvar/variation/10315/

CAID: CA255208

gnomAD: Not reported

Case#: 7

DiseaseAssertion: Hemophilia A

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVIII:C 34/30/35% (Mild Phenotype), No inhibitors present

CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing

Gene: F8

Variant: NM_000132.3:c.1010-842G>A

ClinVar: NA

CAID: CA337336857

gnomAD: MAF in Ashkenazi Jewish population 0.01105<br>https://gnomad.broadinstitute.org/variant/X-154195804-C-T

Case#: 99, male, 9 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6544C>T

LegacyVariant:

ClinVar: 10321

CAID: CA255214

gnomAD:

Case#: 92, male, 61 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 4.2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6440G>T

LegacyVariant:

ClinVar: No

CAID: CA414908004

gnomAD:

Case#: 106, male, 12 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6683G>A

LegacyVariant:

ClinVar: 10098

CAID: CA255016

gnomAD:

Case#: 54, male, 9 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 17%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1834C>T

LegacyVariant:

ClinVar: 10236

CAID: CA255129

gnomAD:

PMID: 29399993

Gene: F8

HGNC: 3546

InsufficientEvidence: This article mentions variants however there are no specific case reports mentioned therefore, insufficient evidence

Case#: N/A

DiseaseAssertion: Moderate/Mild Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.82T>C (p.Cys28Arg)

ClinVar: 10657

CAID: CA255450

Case#: N/A

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: N/A

CaseHPOsFreeText: N/A

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.62G>T ((p.Gly21Val)

ClinVar: Absent

CAID: CA414434385

gnomAD: Absent/NotReported

Case#: Patient R (male, 83 y/o)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858, HP:0012233

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 2.4%), extensive subcutaneous bleeding

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

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

ClinVar: Absent

CAID: CA414435437

gnomAD: Allele Frequency (European-non Finnish): 0.00002186

Case#: 8

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.422G>A

LegacyVariant:

ClinVar: No

CAID: CA414438897

gnomAD:

Case#: Cz37, Italy (Calabria)

DiseaseAssertion: Hemophilia A

FamilyInfo: Inherited

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FVII:C <1%

CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method

Gene: F8

Variant: NM_000132.3:c.4379dup (p.Asn1460LysfsTer2)

ClinVar: NA

CAID: CA645292749

gnomAD: MAF for p.Asn1460LysfsTer2 in the European (non-Finnish) population 0.00001245<br>https://gnomad.broadinstitute.org/variant/X-154157685-A-AT

PMID: 31264916

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

Case#: Khan_2019_proband_1, male, age 8 years at time of report, national origin reported as Emirati

CasePresentingHPOs: HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000577 (Exotropia), HP:0007663 (Reduced visual acuity), HP:0410280 (Pediatric onset), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: The patient has been diagnosed with childhood-onset rod-cone dystrophy with early macular involvement.

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of a retinal dystrophy gene panel.

CaseMethod1: retinal dystrophy gene panel

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

CaseGenotypingMethod: Genotyping consisted of a retinal dystrophy gene panel followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.189dup (p.Gln64fs) variant in the homozygous state.

ClinVar: 978976

gnomAD: The variant was found in gnomAD v2.1.1.

VariantEvidence: NM_016247.4(IMPG2):c.189dup (p.Gln64fs) is a frameshift variant in exon 2 of 19 that is predicted to trigger NMD or to at least truncate the C-terminal 95% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant.

CasePMIDs: N/A

ExperimentName: Defective lysosomal sorting receptor degradation in CLN5-depleted HeLa cells

NonPatientCell: HeLa cells (EFO:0001185)

GeneFunction: Lysosomal organization (GO:0007040)

GeneAlteration: CLN5 (or the CLN1 control) was depleted by transient transfection of small interfering RNA (siRNA) into HeLa cells, 48 hrs. before assays were performed.

FunctionalEvidence: CLN5-depleted cells have reduced immunofluorescent signal (Fig. 2K) and reduced expression (Fig. 3A) of two lysosomal sorting receptors; cation-independent mannose 6-phosphate receptor (CI-MPR) and sortilin (Fig. 2K). CLN5-depleted cells also have fragmented TGN46 signal (Fig. 2Q) and increased precursor and intermediate forms of the lysosomal cargo protein cathepsin D (Fig. 3C). These findings are consistent with CI-MPR and sortilin failing to correctly recycle to the Golgi and being degraded in lysosomes instead, possibly due to a defect in a complex called retromer, which returns membrane-associated proteins from the endosome to the Golgi or other cellular compartments. Endosomal signal for the retromer subunit Vps26 is also decreased (Fig. 4E), and both Vps26 and Vps35 are increasingly cytosolic rather than membrane-bound in CLN5-depleted cells (Fig. 6A). These defects are reversed by exogenously expressing CLN5 (Fig. 7B). Rab7 recruitment to the endosome is also defective in CLN5-depleted cells (Figs. 8B,8M). Considering that CLN5 interacts with Rab5 and Rab7 (Fig. 9A), it may serve as a scaffold recruiting Rab7 and the retromer complex to the endosomal membrane, for the purpose of recycling membrane-associated receptors such as sortilin and CI-MPR out of the endosome. Thus, patients with CLN5 loss-of-function variants may have defective recruitment of the retromer complex to the lysosome / endosome and disordered trafficking of membrane proteins out of these compartments as a result.

FAVariants: N/A

PMID: 12579474

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 9257651

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Case#: Jespersgaard_2019_Patient_167, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.627+2T>G variant in the homozygous state.

ClinVar: 636057

gnomAD: The NM_000440.3(PDE6A):c.627+2T>G variant is not found in gnomAD v2.1.1.

VariantEvidence: The NM_000440.3(PDE6A):c.627+2T>G variant disrupts a canonical splice site in intron 2, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_162, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants in the compound heterozygous state.

ClinVar: 636052, 636051

gnomAD: The NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants are not found in gnomAD v2.1.1.

VariantEvidence: NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) are nonsense variants in exons 10 and 7, respectively. They are predicted to result in nonsense-mediated decay or at least to respectively truncate the C-terminal ~59% or ~50% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 30718709

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.

Penetrance: Known disease-causing alleles appear to be completely penetrant.

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

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

ClinVar: 636053

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

ExperimentName: Mouse model with hemizygous disruption of the GPR143 ortholog Oa1

NonHumanModel: Mus musculus

GeneAlteration: A hemizygous mouse model of Oa1 knockout was generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection.

ModelPhenotype: HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting), Giant melanosomes in retinal pigment epithelial cells

HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)

ModelEvidence: Although the coat, eye color, and ERG responses of the mice were unaffected, the mice match the human patients in that they exhibit hypopigmentation of the fundus (Fig. 2), optic fiber misrouting at the chiasm, and expansion of individual melanosomes into giant melanosomes within cells of the RPE (Figures 2, 3). The mice match the mode of inheritance from the human patients.

ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.

PMID: 11092754

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

PMID: 28041643

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

ExperimentName: Chlamydomonas mutant model of IFT140 loss-of-function

NonHumanModel: Chlamydomonas reinhardtii

GeneAlteration: The Ift140 mutant model has disruption of the Chlamydomonas gene by insertion of the paromomycin resistance gene AphVIII between bases 8234 and 8235 of the IFT140 gene (in exon 21 of 28).

ModelPhenotype: The mutant exhibits short flagella due to slower flagellar regeneration as well as absence of IFT43 and IFT122 (IFT-A proteins) from the peri-basal body (shown by immunofluorescent co-localization with α-tubulin).

HumanPhenotype: The human patients exhibit the absence of cilia from fibroblasts

ModelEvidence: The cellular defects of the model in flagellar regeneration/assembly (Figures 6A,6C) parallel the absence of cilia from a high proportion of patient fibroblasts. The model also helps explain this defect by showing the underlying cause; the absence of IFT-A complex components from the peri-basal body region (Figure 5E-5F).

ModelVariant: The model does not feature any of the variants observed in human patients.

PMID: 28207750

Gene: IFT140

HGNC: 29077

Disease: Short-rib thoracic dysplasia 9 with or without polydactyly

MONDO: 0009964

InheritancePattern: autosomal recessive

Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.

Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.

Case#: Holmberg_Patient_6, male, age 2 at onset and age 13 at death, Dutch 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:0011421 (Death in adolescence), 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)

CaseHPOFreeText: This patient exhibited the most rapid clinical course from the group of 8 patients. Age of onset was 2, while mental decline was present at age 3 and visual deterioration at age 5. Ataxia, seizures, and abolished electroretinogram were found at age 7. Loss of independent walking occurred at age 8. 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:0001312 (Giant somatosensory evoked potentials)

CaseNotHPOFreeText: Flash visual evoked potential (fVEP) was found to be normal at age 7.

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.688G>A (p.Asp230Asn) variant.

ClinVar: 2566 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A

VariantEvidence: NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) is a recurring missense variant that has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Holmberg_Patient_8, female, age 3 at onset and age 19 at time of study, Swedish 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: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), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)

CaseHPOFreeText: Age of onset was 3, while mental decline was found at age 7. Visual deterioration and Seizures developed at age 8. Ataxia and Giant flash visual evoked potentials had onset at age 9. 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. Cerebral atrophy was slight at age 8.9 years, but had progressed to severe cerebral and cerebellar atrophy by age 17.

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 a compound heterozygote harboring the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.

ClinVar: 2565, 56543

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A 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.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5. NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is 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

GroupName: Holmberg_Group_1

GroupPresentingHPOs: 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: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)

GroupHPOFreeText: 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.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

NumberMales: 4

NumberFemales: 4

CountryOrigin: Finland / Sweden / Netherlands

Ethnicity: Finnish / Swedish / Dutch

Race: Not mentioned

AgeRange: 2-4 years old at onset, 7-19 years old at time of study

TotalNumber: 8

FamilyInfo: 0

NoFamily: 8

VariantCount: 8

NonVariant: 0

OtherVariant: 0

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

GroupMethod1: N/A

GroupMethod2: N/A

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

GroupAddInfo: N/A

Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 at time of study, Finnish origin

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

CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: N/A

CaseMethod2: N/A

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

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.

ClinVar: 2565 (homozygous)

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

ExperimentName: Mouse knockout model of Rpgr loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The model has targeted hemizygous (male) or biallelic (female) disruption of the mouse Rpgr gene by insertion of a neomycin resistance cassette to replace exons 4 through 6 with a resistance cassette and generate a null variant.

ModelPhenotype: HP:0030612 (Abnormal retinal morphology on macular OCT), partial mislocalization of blue and green cone opsins to the inner segment, reduced rhodopsin content in the outer segment, HP:0000546 (Retinal degeneration), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0030610 (Photoreceptor outer segment loss on macular OCT), disorganization of disk membranes, normal connecting cilia morphology, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram),

HumanPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)

ModelEvidence: The model has been well-characterized at the ocular level and triggers molecular and photoreceptor cell defects (Figures 4a, 4b, 5, 6, 7a, and 7b) that are consistent with human patient features such as night blindness, central visual field loss, and peripheral visual field loss.

ModelVariant: The model does not feature a variant equivalent to one observed in human patients.

PMID: 10725384

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).

Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.

Case#: Georgiou_2024_Family_GC29680_Proband_P09, female, reported at age 30 years, family origin reported as from Bangladesh

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)

CaseHPOFreeText: BCVA began at 0.39 logMAR and progressed to 0.54 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) variant in the homozygous state.

ClinVar ID: 3675731

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001098 (1 / 91070) in the South Asian population https://gnomad.broadinstitute.org/variant/chr10-47357112-T-G?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) is a nonsense variant within exon 4 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

Case#: Georgiou_2024_Family_GC19393_Proband_P06, female, reported at age 14 years, family origin reported as from Pakistan

CasePresentingHPOs: HP:0011003 (High myopia), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)

CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.30 logMAR.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.

CaseMethod1: NGS panel / WES / WGS

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.160C>T (p.Gln54Ter) variant in the homozygous state.

ClinVar ID: 964958

gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0003184 (29 / 91094) in the South Asian population https://gnomad.broadinstitute.org/variant/10-47348644-C-T?dataset=gnomad_r4

VariantEvidence: NM_002900.3(RBP3):c.160C>T (p.Gln54Ter)) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.

CasePMIDs: N/A

PMID: 30628748

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

Case#: Wells_1993_Proband_III/5, female, age 44 years at time of first examination, family origin not reported

CasePresentingHPOs: Adult onset HP:0003581, Visual impairment HP:0000505, Subretinal deposits HP:0031528, Abnormal light-adapted single flash electroretinogram HP:0030472.

CaseHPOFreeText: The proband has been diagnosed with adult vitelliform macular dystrophy, with onset in the mid-thirties. Foveal deposits are small, yellow, and at the RPE level.

CaseNotHPOs: Abnormal light-adapted flicker electroretinogram HP:0030473

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of PRPH2

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing of this family consisted of screening of the RHO locus for variants causing RP, with negative results. Genotyping was performed by Sanger sequencing of the PCRs product to identify the variant.

Variant: The proband harbors the NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant in the heterozygous state.

ClinVar ID: 98707

gnomAD: The NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant was not found in gnomAD v4.0.0.

VariantEvidence: NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) is a nonsense variant in exon 2 of 3 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 26% of the protein product.

CaseAddInfo: Although the proband is the only family member genotyped and examined by the authors, her father was confirmed to be similarly affected. Family consanguinity was not reported.

CasePMIDs: N/A

Case#: Xin_Patient_9, sex not mentioned, age 6 at onset, U.S. nationality, Egyptian ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003736 (Autophagic vacuoles)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 6). Cognitive regression, Seizures, and Visual loss had onset at age 7. EM finding of vacuoles was made specifically in muscle.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant.

ClinVar: 56546 (homozygous)

gnomAD: The NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant is absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 is a frameshift variant that disrupts ~28% of the protein product.

CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.

CasePMIDs: N/A

Case#: Xin_Patient_2, sex not mentioned, age 5-6 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.

ClinVar: 56544

CAID: CA2017997733

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)

CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.

ClinVar: 56542, 56526

gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.

VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: N/A

GroupName: Xin_2010_Group_1

GroupPresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration)

GroupNotHPOs: N/A

NumberMales: Not mentioned

NumberFemales: Not mentioned

CountryOrigin: United States (9 patients) or Sweden (1 patient)

Ethnicity: The 10 patients had various ethnicities; Admixture of French Canadian / Irish / U.K. / Dutch, Admixture of European non-Finnish (3 individuals), Hispanic, Chinese, Indian, Egyptian, Pakistani, Swedish

Race: Not mentioned

AgeRange: Between 4 and 17 years of age at onset

TotalNumber: 10

FamilyInfo: 0

NoFamily: 10

VariantCount: 10

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

GroupMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

GroupMethod2: as mentioned

GroupGenotypingMethod: 47 original patients with an NCL phenotype but no variant in one of the 5 tested loci were subjected to CLN5 genotyping. PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. 10 patients were identified as harboring CLN5 variants. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

GroupAddInfo: N/A

ExperimentName: Mouse homozygous mutant model of partial IFT140 loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: The Cauli mouse model has biallelic disruption of the mouse Ift140 gene introduced by mutagenesis using N-ethyl-N-nitrosourea. The mutation is a missense change is c.2564T>A (p.Ile855Lys) in Ift140.

ModelPhenotype: HP:0034241 (Prenatal death), HP:0030769 (Exencephaly), HP:0002414 (Spina bifida), HP:0001999 (Abnormal facial shape), HP:0002648 (Abnormality of calvarial morphology), HP:0011297 (Abnormal digit morphology), HP:0001627 (Abnormal heart morphology), HP:0033334 (Abnormal embryonic development, specifically defects in somite patterning), HP:0000528 (Anophthalmia), HP:0001829 (Foot polydactyly), HP:0000194 (Open mouth), HP:0000772 (Abnormal rib morphology), HP:0000896 (Rib exostoses), HP:0001789 (Hydrops fetalis), HP:0001654 (Abnormal heart valve morphology), HP:0010290 (Short hard palate),

HumanPhenotype: HP:0001156 (Brachydactyly), HP:0010579 (Cone-shaped epiphysis), HP:0000556 (Retinal dystrophy), HP:0001591 (Bell-shaped thorax), HP:0000773 (Short ribs), HP:0000107 (Renal cyst), HP:0001252 (Hypotonia), HP:0001263 (Global developmental delay), HP:0001363 (Craniosynostosis), HP:0005054 (Metaphyseal spurs), HP:0010454 (Acetabular spurs), HP:0000083 (Renal insufficiency), HP:0002093 (Respiratory insufficiency), absent cilia in fibroblasts

ModelEvidence: The mode of inheritance in this model matches the biallelic/homozygous mode of inheritance observed in human disease. While the defects in the mouse model are more severe than those of the human patients, shared features include rib cage anomalies (Figure 2), digit anomalies (Figure 4), disruption of eye development (fully penetrant, described in text only), and severe morphological anomalies of the primary cilia in the limb buds (Figure 1G). While the model was generated using a mutagen, it is important to note that the targeted homozygous null mutant in Ift140 recapitulates the features of the model, albeit with enhanced severity. This confirms that the model's mechanism of pathogenicity is incomplete loss of Ift140 function. The localization of Ift140 protein to the base and tip of primary cilia in the limb bud is also consistent with the known function in humans (Figure 5F).

ModelVariant: The model does not feature any of the variants observed in human patients. Instead, the mutation is a missense change, c.2564T>A (p.Ile855Lys) in Ift140. The corresponding residue in human IFT140 is Thr854.

Mouse model based on ERG defects induced by Kcnj13 shRNA injection (packaged in lentiviral particles)

PMID: 15459177

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Shroyer_1999_Proband_AR534-07, female, age 68 years at time of diagnosis, family origin from the United States (Utah or Boston)

CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration), HP:0003584 (Late onset)

CaseHPOFreeText: The proband has been diagnosed with exudative age-related macular degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of ABCA4

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

Variant: The proband harbors the NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) variant in the heterozygous state.

ClinVar ID: 7904

gnomAD: The variant is found in gnomAD v4.1.0 at frequencies of 0.0003059 in the European (non-Finnish) population and 0.001723 in the Ashkenazi Jewish population. https://gnomad.broadinstitute.org/variant/1-94031110-G-A?dataset=gnomad_r4

VariantEvidence: NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) is a missense variant without functional evidence of a damaging impact on ABCA4.

CaseAddInfo: The proband is the grandmother of four patients with a diagnosis of Stargardt disease. Her 52-year-old daughter carries the same variant but is unaffected (normal fundus).

CasePMIDs: N/A

PMID: 32265257

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

PMID: 10854443

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

Case#: Olivier_2021_Family_C_Proband_II:1, female, age 48 years at the time of diagnosis, national origin reported as Spanish

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0030329 (Retinal thinning), HP:0007737 (Bone spicule pigmentation of the retina)

CaseHPOFreeText: The proband was diagnosed with moderate retinitis pigmentosa at age 48 years.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using gene panel testing and Sanger sequencing-based confirmation

CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus, Sanger sequencing-based confirmation, and haplotype analysis of the multiple families harboring the variant.

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

ClinVar ID: 1240018

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.

CaseAddInfo: This family helps establish the incomplete penetrance of the variant, as the patient's carrier mother was clinically asymptomatic with no retinal vessel abnormalities, despite the presence of hard drusen-like deposits in the macula.

CasePMIDs: N/A

Case#: Olivier_2021_Family_B_Proband_II:2, female, age not specified, ethnic origin reported as French

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0030643 (Vitelliform-like retinal lesions), HP:0011506 (Choroidal neovascularization),

CaseHPOFreeText: The patient has a diagnosis of vitelliform macular dystrophy, and reportedly has a hyperreflective deposit in one eye.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0030454 (Abnormal electrooculogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.

CaseMethod1: Screening of IMPG1 using gene panel testing and Sanger sequencing-based confirmation

CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.

CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus, Sanger sequencing-based confirmation, and haplotype analysis of the multiple families harboring the variant.

Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.

ClinVar ID: 1240018

gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T

VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.

CaseAddInfo: This family has helped establish the incomplete penetrance of the variant, as the patient's two sisters were asymptomatic carriers with normal fundus findings at ages 45 and 50 years respectively. The patient's 70-year-old mother was also a carrier and exhibited low vision.

CasePMIDs: N/A

ExperimentName: Morpholino-based disruption of Impg1 in medaka fish

NonHumanModel: Oryzias latipes

GeneAlteration: Model animals were subjected to targeted disruption of Impg1 by morpholino-based silencing.

ModelPhenotype: HP:0030610 (Photoreceptor outer segment loss on macular OCT).

HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

ModelEvidence: Morpholino-injected animals exhibit decreased photoreceptor outer segment length, especially for cones (Figures 4I, 4J).

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg1 ortholog using a morpholino.

Case: Felbor_1995_Family_1_patient_1, gender and age not specified, German-Czech family origin

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Family pedigree (from microsatellite-based linkage testing) mapping the disease locus to chr22q13-qter is shown in Figure 1.

CasePresentingHPOs: HP:0030666 (Retinal neovascularization), HP:0007777 (Chorioretinal scar), HP:0000603 (Central scotoma), HP:0000556 (Retinal dystrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000630 (Abnormal retinal artery morphology), HP:0030491 (Choriocapillaris atrophy), HP:0007994 (Peripheral visual field loss), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseHPOFreeText: Patients were considered to exhibit early-onset SFD with a mean age of 25. The presenting symptom was central subretinal neovascularisation, which preceded extensive scarring. Second eye involvement generally occurred months later, indicating rapid progression. Retinal dystrophy was reported to be tapetal. Intraretinal arteries were attenuated. Dark adaptation was decreased.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Genetic linkage testing / genotyping of affected and unaffected family members with three microsatellite markers that were previously associated with SFD and that flank the TIMP3 locus. This was followed by single-stranded conformational polymorphism (SSCP) of all five TIMP3 exons, detecting a mobility shift in exon 5.

CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) is a missense variant predicted to substitute a new cysteine residue into exon 5.

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

VariantEvidence: This variant substitutes an additional cysteine residue into the C-terminal region encoded by TIMP3 exon 5. Additional variant evidence is presented in PMID:10854443 and PMID:16223891.

PMID: 19074807

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).

Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.

FamilyLabel: Kelsell_1998_CORD6_Family

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

Family#PresentingHPOFreeText: Central vision was lost before age 7, while peripheral field vision was lost by the fourth decade of life. Cone ERG was undetectable early on in the disease, while rod ERG abnormalities later developed progressively.

FamilyNotHPOs: N/A

CountryOrigin: British

Ethnicity: N/A

Race: N/A

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

Family#Method1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus

Family#Method2: HhaI restriction digest of the PCR-amplified exon 13

Family#GenotypingMethod: 10 unspecified affected and some unaffected family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. For each affected and unaffected family member, the PCR-amplified product from exon 13 was subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.

Affected: 14

Unaffected: 19

Segregations: 13 (no consanguinity mentioned), Figures 1A and 1B

PublishedLOD: 5.93 (PMID: 9097965)

eLOD: 4.2

AddSegregationInfo: All segregations were consistent with the proposed gene-disease association and complete penetrance.

ProbandLabel: Kelsell_1998_CORD6_Family_Proband_2

Variant: NM_000180.3(GUCY2D):c.[2511G>C;2512C>A]

ClinVar: 453243

gnomAD: The variant was not found in gnomAD.

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

FamilyPMIDs: PMID: 9097965, PMID: 10647719

Case#: Morimura_1998_Family_9404_Patient_II-3, male, age and family origin not specified

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant.

ClinVar: 98861 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant was not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.2T>C (p.Met1Thr) is a missense variant that disrupts the start codon and is therefore predicted to have gene impact.

CaseAddInfo: Other family members were not genotyped, and potential consanguinity between the parents was not reported.

CasePMIDs: N/A

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

CasePresentingHPOs: HP:0000546 (Retinal degeneration)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA

CaseMethod2: Sanger sequencing of all 14 exons of RPE65

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

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

ClinVar: 940479 (homozygous)

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

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

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

CasePMIDs: N/A

ExperimentName: GPR143 interacts with TYR by co-IP and FRET

InteractingGene: TYR, which is implicated in oculocutaneous albinism types 1A and 1B

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation and FRET were both performed with positive results.

InteractionEvidence: Co-IP of the exogenously expressed GPR143 fusion protein or endogenous TYR found that IP of one protein pulls down the other as well (Figure 2). This was confirmed by fluorescent resonance energy transfer experiments (Figures 4 and 5). Use of a mislocalizing GPR143 mutant control showed that TYR localization appears to be GPR143-dependent (Figures 3 and 4).

PMID: 10601738

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.

Selection A - Gene is expressed in tissues relevant to disease:

ExperimentName: IMPG1 protein ("IPM150") expression within eye tissues is localized to cone and rod photoreceptor cells in the outer nuclear layer.

TissueExpression: UBERON:0001789 (outer nuclear layer of retina)

ExpressionEvidence: In situ hybridization within eye tissues detects IMPG1 expression in the cone and rod photoreceptor cells, specifically in the outer nuclear layer (Figure 8).

Case#: Meindl_1996_Family_RP49_Proband, male, age not specified, family origin either German or British

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Disease onset was reported as early.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.

CaseMethod1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations

CaseMethod2: Sanger sequencing of the RPGR locus

CaseGenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) variant in the hemizygous state.

ClinVar: 98794

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

VariantEvidence: NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) is a missense variant in exon 7 of 15 and has been shown to disrupt the ability of the protein product to interact with PDE6D, INPP5E, and RPGRIP1L (PMID: 30622176, Figure 4).

CaseAddInfo: The proband is a member of Family RP49.

CasePMIDs: N/A

FamilyLabel: Meindl_1996_Family_F47

Family#PresentingHPOs: N/A

FamilyPresentingHPOFreeText: Affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Not specified

Ethnicity: Not specified

Race: Not specifically mentioned

Family#PreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.

Family#Method1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations

Family#Method2: Sanger sequencing of the RPGR locus

Family#GenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.

Affected: 3

Unaffected: N/A

Segregations: 8 segregations are shown by the pedigree in Figure 6.

PublishedLOD: N/A

eLOD: 2.4

AddSegregationInfo: N/A

ProbandLabel: Meindl_1996_Family_F47_Proband

Variant: The affected family members harbor the NM_001034853.2(RPGR):c.294C>A (p.His98Gln) variant in the hemizygous state.

ClinVar: 98775

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

VariantEvidence: NM_001034853.2(RPGR):c.294C>A (p.His98Gln) is a missense variant and does not have associated evidence of impact on RPGR function.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 26072023

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.

Penetrance: Penetrance is thought to be complete.

PMID: 35272502

Gene: OPN1LW

HGNC: 9936

Disease: protan color blindness

MONDO: 0010565

InheritancePattern: X-linked

Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).

Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).

PMID: 25475713

Gene: KCNJ13

HGNC: 6259

Disease: Leber congenital amaurosis 16

MONDO: 0013613

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.

Penetrance: Known disease-causing alleles appear to be completely penetrant.

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focused on a panel of 27 LCA genes and 60 recessive retinitis pigmentosa genes. Sanger sequencing of the proband and family members was then performed to confirm the presence of the variant and to test segregation.

Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.359T>C (p.Ile120Thr) variant.

ClinVar: 191155

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

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

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

CasePMIDs: N/A

PMID: 15452577

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).

Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.

Case#: Arno_2015_Family_GC19774_Patient_3, male, first seen at age 2 years, family origin not reported

CasePresentingHPOs: HP:0025313 (Exophoria), HP:0000545 (Myopia), HP:6001439 (Tigroid fundus), HP:0012795 (Abnormal optic disc morphology, specifically myopic discs), HP:0007663 (Reduced visual acuity), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0030844 (Undetectable pattern electroretinogram)

CaseHPOFreeText: BCVA was 0.350 / 0.325 logMAR (Snellen 20/50 or 20/40). OCT showed loss of inner segment-ellipsoid over peripheral macular areas. Initial ERG showed rod more affected than cone. Later ERG showed more severe cone deterioration. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) variant in the homozygous state.

CAID: CA376670175

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected younger sibling sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Arno_2015_Family_GC17452_Patient_2, female, first seen at age 4 years, family origin not reported

CasePresentingHPOs: HP:0011003 (High myopia), HP:0000662 (Nyctalopia), HP:0030534 (Abnormal best corrected visual acuity test), HP:6001439 (Tigroid fundus), HP:0030602 (Abnormal fundus autofluorescence imaging, specifically patchy increased FAF in the vascular arcades), HP:0030603 (Abnormal optical coherence tomography, specifically showing loss of inner segment-ellipsoid over peripheral macular areas), HP:0008275 (Abnormal light-adapted electroretinogram, specifically showing delay and amplitude reduction of cone responses)

CaseHPOFreeText: BCVA was 0.550 / 0.575 logMAR (Snellen 20/80). FAF showed increased signal in vascular arcades, OCT showed loss of inner segment-ellipsoid over peripheral macular areas, ERG showed delay and amplitude reduction of cone responses. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was by whole exome sequencing.

CaseMethod1: WES

CaseMethod2: Sanger sequencing of RBP3

CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.

Variant: The individual harbors the NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) variant in the homozygous state.

CAID: CA376677245

gnomAD: The variant was not found in gnomAD version 4.1.1.

VariantEvidence: NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) is a nonsense variant within exon 4 of 4 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.

CaseAddInfo: The proband comes from a consanguineous family with a similarly affected older sibling sharing the same homozygous genotype.

CasePMIDs: N/A

FamilyLabel: Perrault_2000_Family_9

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

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

Family#Method1: Sanger sequencing of PCR products from each of the 20 exons

Family#Method2: N/A

Family#GenotypingMethod: Family members were initially subjected to homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.

Affected: 4

Unaffected: 2

Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.

PublishedLOD: N/A

eLOD: 2.06

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_9_Proband

Variant: Affected individuals are homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.

ClinVar: 9350

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

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 9350

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

PMID: 12567324

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

Case#: Badano_2003_Family_KK26_Proband_05, gender, age, and origin not reported.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome. Specific phenotypes have not been described in detail.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of linkage mapping using a 10-cM linkage map set to identify regions of homozygosity unique to the affected family member only.

CaseMethod1: Homozygosity analysis

CaseMethod2: Sanger sequencing of the BBS7 locus

CaseGenotypingMethod: Genotyping first identify regions of homozygosity unique to the affected family member, then performed Sanger sequencing of the BBS7 locus.

Variant: The patient harbors the NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant in the homozygous state.

ClinVar ID: 3017

gnomAD: The NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_176824.3(BBS7):c.709_712del (p.Lys237fs) is an out-of-frame deletion variant in exon 7 of 18 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 67% of the protein product.

CaseAddInfo: The proband is a member of family KK26, which is known to be consanguineous. The proband has two unaffected carrier parents, 5 unaffected carrier siblings, and 1 unaffected non-carrier sibling.

CasePMIDs: N/A

Selection A- Gene is expressed in tissues relevant to disease:

ExperimentName: Wild-type Prph2 localizes to mouse rod outer segments.

TissueExpression: photoreceptor outer segment layer (UBERON:0003926)

ExpressionEvidence: Western blotting with an anti-Prph2 antibody confirms that Prph2 is present in retinal outer segments and exists a a dimer (Fig. 2), although other control tissues are absent.

ExperimentName: AAV8-Nr2e3 rescue of rd7/rd7 mice

RescueModel: Mus musculus

GeneAlteration: Rescue was performed by subretinal injection of AAV8-Nr2e3 (or no treatment) into rd7/rd7 mice with homozygous disruption of endogenous Nr2e3

RescueVariant: No variant form of Nr2e3 was studied in this rescue experiment.

RescuePhenotype: The rescued phenotype is retinal spots in the fundus (Figure 3).

RescueMethod: This rescue model has introduction of the virally packaged mouse wild-type Nr2e3 gene.

RescueEvidence: Subretinal administration of the gene results in considerable improvement of the retinal spots in the fundus compared with untreated eyes 3 months post-injection (Figure 3).

ModelVariant: The model harbors homozygous out-of-frame deletion of 380 bp within the coding region of Nr2e3.

PMID: 33531964

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.

Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.

PMID: 12515581

Gene: GPR143

HGNC: 20145

Disease: X-linked recessive ocular albinism

MONDO: 0021019

InheritancePattern: X-linked recessive

Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)

Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.

Case#: Hejtmancik_2008_Family_55001_Proband, sex and age not specified, family origin described as American of European ancestry

CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, Corneal guttata HP:0012038, Presenile cataracts HP:0007819, Abnormal vitreous humor morphology HP:0004327, Retinal detachment HP:0000541

CaseHPOFreeText: All family members have been diagnosed with Snowflake vitreoretinal degeneration between the ages of 12 and 85 years of age. Please note that detailed phenotypes were found in PMID: 14644728, and included fibrillar vitreous degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Orofacial features, early-onset hearing loss, and arthritis were absent.

CasePreviousTesting: The proband was previously subjected to linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460).

CaseMethod1: linkage analysis

CaseMethod2: Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2

CaseGenotypingMethod: The family was previously genotyped by linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460), followed by Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2.

Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.

ClinVar: 6585

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4

VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (Figure 2).

CaseAddInfo: The proband's family includes 12 other affected individuals carrying the variant, and 14 unaffected individuals (as well as 4 unaffected spouses) without the variant.

CasePMIDs: PMID: 15557460, PMID: 14644728

PMID: 9888420

Gene: RBP4

HGNC: 9922

Disease: progressive retinal dystrophy due to retinol transport defect

MONDO: 0014060

InheritancePattern: autosomal recessive

Prevalence: RBP4-related cases have an estimated prevalence of less than 1 in 1,000,000 (https://www.orpha.net/en/disease/detail/352718?search=&mode=name)

Penetrance: RBP4 disease-causing variants appear to have complete penetrance in biallelic cases.

PMID: 18408187

Gene: TIMP3

HGNC: 11822

Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy

MONDO: 0007640

InheritancePattern: Autosomal Dominant

Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)

Penetrance: Fully penetrant, onset between the third and sixth decades of life

ExperimentName: Two dog models of Rpgr loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: The two models have disruption of the dog Rpgr gene by the c.1028_1032del frameshift variant or the c.1084_1085del frameshift variant, respectively.

ModelPhenotype: Normal photoreceptors until young adulthood in one model, HP:0000546 (Retinal degeneration), Photoreceptor outer segment cell degeneration, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram), relative sparing of cones in both models, HP:0000618 (Blindness)

HumanPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)

ModelEvidence: The two models have been well-characterized at the ocular level and exhibit ERG abnormalities (Fig. 4IB1-3) and degeneration of visual cells and outer segment disorganization, leading to end-stage retinal disease (Fig.4IIE-4IIH). These phenotypes are consistent with human patient features such as night blindness, central visual field loss, and peripheral visual field loss.

ModelVariant: The models study naturally occurring variants that do not have equivalent / orthologous variants reported in human patients.

ExperimentName: Naturally occurring bbs-7 loss-of-function C. elegans model

NonHumanModel: C. elegans

GeneAlteration: The model animals harbor a naturally occurring homozygous nonsense variant at nucleotide 2899 within the bbs-7 locus.

ModelPhenotype: short cilia, defective chemotaxis, defective intraflagellar transport, IFT mislocalization

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

ModelEvidence: This is a naturally occurring C. elegans model of biallelic bbs-7 disruption. The mutant animals exhibit reduced chemotaxis (dependent on two chemosensory neurons, Figure 2E), shorter cilia (Figure 3), defective localization of IFT particles (Figure 4), and reduced intraflagellar transport (Figure 5). Rescue of chemotaxis with expression of the wild-type C. elegans bbs-7 gene directly linked the defect with bbs-7 (Figure 2E).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring and apparent null variant disrupting bbs-7 expression.

PMID: 15231740

Gene: BBS7

HGNC: 18758

Disease: Bardet-Biedl syndrome 7

MONDO: 0014435

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.

PMID: 16670814

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.

Penetrance: Penetrance is thought to be complete.

PMID: 29947567

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 87 with choroidal involvement

MONDO: 0032873

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.

Penetrance: Incomplete penetrance, estimated at 80%

FamilyLabel: Gliem_2015_Family_2

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset of symptoms in the early fifth or sixth decade of life, with either dark adaptation problems, metamorphopsia, or visual loss being the first symptoms, central and midperipheral atrophy, central fibrosis. Some affected family members were largely asymptomatic into the 6th decade of life, but had central retinal drusen. Choroidal neovascularization was observed in some family members and appeared to be a driver of vision loss.

FamilyNotHPOs: HP:0000662 (Nyctalopia)

FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms

CountryOrigin: Germany

Family#PreviousTesting: N/A

Family#GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

Affected: 6

Unaffected: 2

Segregations: 12

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_2_patient_V.1

Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Some of the family members were previously identified by genotyping as having Sorsby fundus dystrophy (PMID:25390527), and are more extensively phenotypically described in this study.

FamilyPMIDs: PMID:25390527

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

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