FamilyLabel: Tabata_1998_Family_Ch

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000529 (Progressive visual loss)

FamilyHPOFreeText: Onset of decreased central vision was seen in the 6th or 7th decade of life (between the ages of 52 and 66), although abnormal findings on ophthalmoscopy (early macular degeneration) found in 4th decade of life.

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was progressively lost, peripheral fundi remained uninvolved and affected individuals continued to walk unguided into the 8th decade of life and beyond.

CountryOrigin: Japan

Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

Family#GenotypingMethod: Sanger sequencing

Affected: 2

Unaffected: 3

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ch_patient_1

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.

FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).

FamilyPMIDs: N/A

Case: Tabata_1998_Family_Ue_patient_1, female, 73 years of age at onset of visual symptoms, country of origin Japan

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: The proband has two affected siblings. All three were subjected to genotyping.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar), HP:0000603 (Central scotoma), HP:0030496 (Macular exudate), HP:0030506 (Yellow/white lesions of the retina), HP:0025243 (Subretinal hemorrhage), HP:0000580 (Pigmentary retinopathy), HP:0030491(Choriocapillaris atrophy)

CaseHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (both eyes between the ages of 73 and 77).

CaseNOTHPOs: HP:0007994 (Peripheral visual field loss), HP:0000512 (Abnormal electroretinogram), HP:0000662 (Nyctalopia)

CaseNOTHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved. Patient had no difficulties with daily activities.

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.

PMID: 9760202

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: 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.

PMID: 10750831

Gene: RBP3

HGNC: 9921

Disease: retinitis pigmentosa 66

MONDO: 0014093

InheritancePattern: autosomal recessive

Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).

Penetrance: RBP3 disease-causing variants appear to have complete penetrance.

Case#: Manes_2013_Family_NAX1_Proband_II:2, female, age unreported, national origin reported as French

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0032037 (Mildly reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)

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

CaseNotHPOs: HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0008275 (Abnormal light-adapted electroretinogram)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.

CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.

Variant: The proband harbors the NM_001563.4(IMPG1):c.1824+1G>A variant in the heterozygous state.

ClinVar: 1240018

gnomAD: The NM_001563.4(IMPG1):c.1824+1G>A variant was found in gnomAD v2.1.1 at a frequency of 0.00002980 (1/33554) in the Latino / Admixed American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660278-C-T?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.1824+1G>A is a canonical splice site variant in intron 13 that does not have evidence confirming an impact on the gene product, however, it has been reported by the same researchers in a proband with retinitis pigmentosa (PMID: 32817297).

CaseAddInfo: The proband has two unaffected sisters and an unaffected mother who share the same genotype. Consanguinity is not reported in this family. It is possible that the proband harbors a second unidentified variant in trans, inherited from the father.

CasePMIDs: N/A

Case#: Morimura_1998_Family_7775_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.271C>T (p.Arg91Trp) variant.

ClinVar: 13115 (homozygous)

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A

VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's mother revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) in a heterozygous state. The father was not genotyped. Potential consanguinity between the parents was not reported.

CasePMIDs: N/A

Case#: Morimura_1998_Family_9148_Patient_II-1, 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 compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants.

ClinVar: 98830, 98875

gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant has a maximum allele frequency of 0.00009643 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68912520-C-T The NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variant has a maximum allele frequency of 0.00009925 (within the Ashkenazi Jewish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68906635-G-A

VariantEvidence: The paternal NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) and maternal NM_000329.3(RPE65):c.544C>T (p.His182Tyr) variants are missense variants that do not have evidence of gene impact.

CaseAddInfo: Genotyping of family members revealed the two variants to be in trans. The brother of the proband shares the same genotype and diagnosis of Leber congenital amaurosis.

CasePMIDs: N/A

PMID: 9501220

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

Case#: Morimura_1998_Family_3867_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 compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variants.

ClinVar: 13115, 98862

gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) variant is not found within gnomAD.

VariantEvidence: NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) is a missense variant that does not have evidence of gene impact. The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant was also detected in this publication in a heterozygous state within two apparently unrelated probands with Retinitis pigmentosa (Figure 2A) and Leber congenital amaurosis (Figure 2B), respectively. A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic.

CaseAddInfo: Genotyping of the proband's parents revealed NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) as the paternal variant and NM_000329.3(RPE65):c.304G>A (p.Glu102Lys) as a de novo variant.

CasePMIDs: N/A

PMID: 11162558

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.

Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.

Case#: Kannabiran _2012_Proband_B-2, male, age 10 years at time of report, national origin from India

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Retinal flecks HP:0012045, Decreased light- and dark-adapted electroretinogram amplitude (rod-cone pattern) HP:0000654, Retinal pigment epithelial atrophy HP:0007722

CaseHPOFreeText: The proband has a diagnosis of autosomal recessive retinitis pigmentosa, with phenotypes highly suggestive of enhanced S-cone syndrome. The proband had gliotic scars in the posterior pole. No OCT was performed, so it is unknown whether macula schisis was present.

CaseNotHPOs: Abnormal optic disc morphology HP:0012795, Abnormal retinal artery morphology HP:0000630, Bone spicule pigmentation of the retina HP:0007737

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of homozygosity mapping, which established linkage to a 41Mb region of chromosome 15, identifying NR2E3 and RLBP1 as the likely candidate loci.

CaseMethod1: Homozygosity mapping within the family of the proband

CaseMethod2: Sanger sequencing of NR2E3 and RLBP1

CaseGenotypingMethod: Genotyping was performed by homozygosity mapping within the family of the proband, followed by Sanger sequencing of NR2E3 and RLBP1.

Variant: The individual harbors the NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) variant in the homozygous state.

ClinVarID: 183143

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

VariantEvidence: NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) is a frameshift variant in exon 2 of 8 that is predicted to introduce a premature stop codon and trigger nonsense-mediated decay.

CaseAddInfo: The proband has two unaffected heterozygous parents and an affected sister who shares the same homozygous genotype.

CasePMIDs: N/A

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

ExperimentName: Immunohistochemical localization of TIMP3 expression to Bruch's membrane and drusen deposits

TissueExpression: Strong expression was observed in Bruch's membrane (UBERON:0003957) and associated drusen, while weak expression was observed in retinal blood vessels (UBERON:0003501).

ExpressionEvidence: TIMP3 was detected in human eye sections (from patients aged 24 to 85 years) using a monoclonal antibody and a TIMP-3 synthetic peptide for specificity. Bruch's membrane was specifically labeled by the antibody (Figure 2B), with strong labeling observed from the RPE to the elastin sublayer. Drusen associated with Bruch's membrane (particularly smaller deposits) also stained strongly for TIMP3 (Figure 2D), while retinal blood vessels showed weak staining as well. Overall, staining was particularly intense in sections from older patients.

Case#: Allen_2003_Familly_X05_Proband, male, age not mentioned, British national origin

CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal OFF response

CasePreviousTesting: N/A

CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F

CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus

CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.

Variant: The proband harbors the NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) variant on the X chromosome.

CAID: CA2573050969

gnomAD: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) was not found in gnomAD.

VariantEvidence: NM_022567.2(NYX):c.1122_*11del (p.Ser374ArgfsTer10) is a frameshift variant in exon 3/3 that is not predicted to trigger NMD but disrupts the C-terminal 22% of the protein product. A separate publication (PMID: 14507859) indicates that variants (such as this one) that remove the C-terminal GPI anchor disrupt NYX function by triggering its mislocalization to and accumulation in the ER and Golgi and its absence from its normal destination at the cell surface. This is a recurrent variant reported here in multiple apparently unrelated British families (X05 and X09).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 29522070

Gene: TRPM1

HGNC: 7146

Disease: congenital stationary night blindness 1C

MONDO: MONDO:0013183

InheritancePattern: autosomal 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 1C specifically is unknown.

Penetrance: Penetrance is thought to be complete.

PMID: 26518167

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#: Xin_Patient_10, sex not mentioned, age 5 at onset, U.S. nationality, Pakistani 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: Motor difficulty was the phenotype at presentation (age 5). Cognitive regression and Seizures had onset at age 5, while Visual loss had onset at age 24.

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.379dup p.Thr127AsnfsTer11 variant.

CAID: CA611398060 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 variant is 0.00003266 (jn the South Asian population, with no homozygotes).

VariantEvidence: NM_006493.4(CLN5):c.379dup p.Thr127AsnfsTer11 is a frameshift variant that disrupts ~65% of the protein product and is likely to trigger nonsense mediated decay.

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#: Haider_2000_Proband_1, male, 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.119-2A>C variant in the homozygous state.

ClinVarID: 191059

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

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped.

CaseAddInfo: The proband is the offspring of 3rd cousins and has an affected sibling and an affected second cousin once removed harboring the variant in the same homozygous genotype (Figure 3c).

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

PMID: 18976725

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

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 caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.

Penetrance: The disease appears to be completely penetrant among published families.

Case: Patient 5

CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.

CasePreviousTesting:

CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.

Variant: 1684+1G>A

ClinVarID: or CAID: CA412915988

gnomAD: variant not present in gnomAD v2.1.1

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

PMID: 21127010

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).

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

Selection A- Gene with same function implicated in disease

ExperimentName: Moye et al. 2018

GOterm: GO:0051179 (localization)

FunctionalEvidence: It was discovered that without ARL2BP, the photoreceptor OS does not develop normally or have correct DMT formation, axoneme extension, and disk alignment.

HGNC: HGNC:10295 (RPGR), HGNC:10263 (RP1), HGNC:6816 (MAK)

GeneEvidence: ARL2BP, RPGR, RP1 and MAK are all localized within the ciliary basal body and rootlet.

SharedGeneImplication: RPGR was classified as having a "definitive" relationship with RP 15 by the Retina GCEP. Refer to the curation for further details. RP1 was classified as having a "definitive" relationship with RP1 by the Retina GCEP. Refer to the curation for further details. MAK was classified as having a "definitive" relationship with MAK-related retinopathy by the Retina GCEP. Refer to the curation for further details.

Case#: Chang_2009_Family_CHRO9_Proband_II:3, female, age 26 years at time of report, family origin not described

CasePresentingHPOs: HP:0000613 (Photophobia), HP:0003593 (Infantile onset), HP:0001141 (Severely reduced visual acuity), HP:0011003 (High myopia), HP:0000551 (Color vision defect, described as complete lack of color discrimination), HP:0000603 (Central scotoma), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram, described as extinguished), HP:0007401 (Macular atrophy)

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

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

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

Variant: The proband harbors the NM_006204.4(PDE6C):c.481-12T>A and NM_006204.4(PDE6C):c.1483-2A>G variants in the compound heterozygous state.

ClinVar ID: 8770, 8771

gnomAD: The NM_006204.4(PDE6C):c.481-12T>A variant was not found in gnomAD v2.1.1. The NM_006204.4(PDE6C):c.1483-2A>G variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.481-12T>A is an intronic variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (use of a cryptic splice site 10 nucleotides upstream, resulting in a frameshift encoding p.Asn161fsX169, Figure S5A). NM_006204.4(PDE6C):c.1483-2A>G is a canonical splice site variant that has been subjected to a mini-gene assay in COS7 cells and triggers a fully penetrant splicing defect (exon 12 skipping, resulting in an in-frame deletion encoding p.495_543del49, Figure S5B).

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

CasePMIDs: N/A

PMID: 9843205

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.

Penetrance: Fully penetrant, with onset typically by 1 year of age

PMID: 11095629

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

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 recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

FamilyLabel: Gu_1997_Family_PMK18

FamilyPresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0001098 (Abnormal fundus morphology)

FamilyPresentingHPOFreeText: Onset is early and course of disease is severe. The appearance of the fundus in adulthood is considered characteristic of retinitis pigmentosa.

FamilyNotHPOs: N/A

CountryOrigin: India

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Previous testing consisted of linkage analysis using microsatellite repeat markers (D152803, DJS1665, D1S438 and DJS1728) associated with the RPE65 locus.

Family#Method1: Linkage analysis

Family#GenotypingMethod: PCR products from affected and control family members were screened by restriction digest analysis using the Msel endonuclease.

Affected: 5

Unaffected: 4

Segregations: 7 segregations were reported, with one inconsistent (patient V-8 is heterozygous while the other affected patients are all homozygous). The pedigree (Figure 1) shows consanguinity between the parents of each affected individual.

PublishedLOD: N/A

eLOD: 2.91

AddSegregationInfo: N/A

ProbandLabel: Gu_1997_Family_PMK18_Patient_V-1

Variant: 4 out of 5 affected individuals are homozygous for the variant.

ClinVar: 98893

gnomAD: The NM_000329.3(RPE65):c.858+1G>T variant is not shown in gnomAD.

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

FamilyPMIDs: N/A

PMID: 15331616

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.

Case#: Bowne_2011_Family_TCD-G_Patient_53, male, unspecified age, family origin in Ireland

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient was initially diagnosed with retinitis pigmentosa prior to genotyping. Detailed phenotypes are not specified for individual patients.

CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Candidate gene sequencing for variants in other known retinitis pigmentosa genes. SNP-based linkage analysis mapped the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. It is not clear whether the patient was one of 3 affected individuals subjected to whole exome sequencing.

CaseMethod1: SNP-based linkage analysis and whole exome sequencing

CaseMethod2: Candidate gene sequencing

CaseGenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.

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

ClinVar: 750796

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

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

CaseAddInfo: N/A

CasePMIDs: PMID: 20861475, PMID: 16799052, PMID: 17982421, PMID: 17924349, PMID: 19520207, PMID: 17003455

FamilyLabel: Bowne_2011_Family_TCD-H

Family#PresentingHPOs: N/A

Family#PresentingHPOFreeText: Family members were provisionally diagnosed with choroideremia prior to genotyping.

FamilyNotHPOs: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Candidate gene sequencing of the CHM locus to exclude the initial diagnosis of choroideremia

Family#Method1: Two-point linkage analysis of the RPE65 locus, as well as haplotype analysis using STR genotypes surrounding the variant of interest

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of the RPE65 locus

Affected: 3

Unaffected: N/A

Segregations: 2 segregations were reported. The pedigree can be found in Figure 1c. Consanguinity of the family was not mentioned.

PublishedLOD: 5.3 (in combination with Family TCD-G, which shares a haplotype

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Bowne_2011_Family_TCD-H_Patient_01

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case#: Family_11850_Proband_II-2, onset before age 7 years, male, seen at a medical center in Guangzhou

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

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

Variant: The individual harbors the NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) variant in the hemizygous state.

CAID: CA3071606830

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

VariantEvidence: NM_020061.6(OPN1LW):c.518_519insC (p.Ala174CysfsTer?) is a nonsense variant in exon 3 of 6 that is predicted to undergo nonsense-mediated decay.

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

CasePMIDs: N/A

Case#: 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#: F2-II:1, F, Age: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0001328 (Specific learning disability/earning difficulties)

CaseHPOFreeText: FAF imaging in three patients demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

OCT imaging also demonstrated loss of outer retina with partial preservation of the inner segment ellipsoid band in patient F2-II:1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). All patients developed posterior subcapsular cataract. Patient F2-II:1 had learning difficulties but no other symptoms suggestive of syndromic disease. There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). Fundus autofluorescence imaging demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

On OCT, there was outer retinal atrophy with variable preservation of photoreceptors most apparent in F2-II:1 with a centrally preserved inner segment ellipsoid band (Fig. 2D). Optical coherence tomography imaging demonstrated intraretinal cysts of the inner nuclear layer, which responded to topical carbonic anhydrase inhibitors (Figs. 2E, 2H, 2K). Electrophysiology demonstrated rod and cone system dysfunction (Table 1).

Two affected siblings from family 2 (GC15894) were homozygous for the missense variant c.323C>G:p.(Pro108Arg).

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Affected sister F2-II:3 was noted to have the following:

Focal parafoveal increased autofluorescence in F2-II:3 (G), likely representing cystoid macular edema.

Very limited photoreceptor preservation for F2-II.3

Focally increased autofluorescence corresponding to macular edema in F2-II:3

CasePMIDs: N/A.

PMID: 18775863

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#: Mancini_2015_Patient_III-6, female, age 52 at onset of visual symptoms, North-West Italian origin

CasePresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia), HP:0000736 (Short attention span), HP:0002075 (Dysdiadochokinesis), HP:0001123 (Visual field defect), HP:0030528 (Paracentral scotoma), HP:0000543 (Optic disc pallor), HP:0002346 (Head tremor)

CaseHPOFreeText: Presentation was at age 52, with visual loss (attributed to glaucoma) as the first phenotype manifested. Pale and excavated optic disc (bilateral) was consistent with severe glaucoma or previous lesion of optic nerve. Neurological symptoms were recognized at age 55 (gait instability, dysarthria, and mild cognitive deficit). Onset of slight attention deficit, nystagmus with vertical component, dysarthric slurred speech, mild head tremor, truncal ataxia, mild dysmetria and dysdiadochokinesia, ataxic gait / posture, brisk deep reflexes in all four limbs, marked cerebellar atrophy (particularly in the vermis), severe bilateral cortical atrophy (especially parietal and temporal), limited visual field (bilateral, with paracentral scotoma in the left eye only), and pale and excavated optic discs (bilateral) were found at age 58. Dysarthria worsened at age 61, when patient also exhibited an inability to walk unassisted, severe intentional tremor in the limbs, and severe cognitive impairment.

CaseNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction), HP:0002353 (EEG abnormality), HP:0040129 (Abnormal nerve conduction velocity),

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.

CaseMethod1: N/A

CaseMethod2: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.

Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.

ClinVar: 183049 (homozygous)

gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A

VariantEvidence: The variant encodes a missense substitution that results in aberrant retention in the ER compartment rather than proper localization to lysosomal vesicles (Figs. 1E-1J).

CaseAddInfo: Family is consanguineous (parents were first cousins).

CasePMIDs: N/A

PMID: 27302685

review article

Case#: Gong_2001_Proband_2, no reported gender, age or national origin

CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

Variant: The patient harbors the NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant in the homozygous state.

ClinVar: 6269

gnomAD: The NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter) is a nonsense variant in exon 6 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~74% of the protein product.

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 8659519

Case#: Aldahmesh_2010_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

PMID: 32203983

GeneName: GNAT2

HGNC: 4394

Disease: achromatopsia 4

MonDO ID: MONDO_0013465

Inheritance: autosomal recessive

FamilyLabel: Corton_2010_Family_RP-72

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with retinitis pigmentosa segregating with an autosomal recessive mode of inheritance.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Spain / Galicia

Ethnicity: Spanish

Race: Not specifically described

Family#PreviousTesting: N/A

Family#Method1: Haplotype analysis

Family#Method2: Sanger sequencing of 3 candidate genes; PDE6A, PDE6B, and RHO

Family#GenotypingMethod: Haplotype analysis was performed in affected and unaffected family members to identify candidate regions of homozygosity in all affected individuals. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A, PDE6B, and RHO loci.

Affected: 4

Unaffected: 5 fully genotyped

Segregations: 4 segregations are shown by the pedigree in Figure 1a.

PublishedLOD: N/A

eLOD: 2.43

AddSegregationInfo: N/A

ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2

Variant: The affected family members harbor the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.

ClinVar: 29874

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T

VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).

FamilyAddInfo: The family includes multiple consanguineous unions, including the proband's parents, and three affected paternal aunts.

FamilyPMIDs: N/A

PMID: 25085631

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.

ExperimentName: Rescue in patient-derived IPSC cells harboring IFT140 variants

RescueProband: Forbes_2018_Proband_1 has been diagnosed with retinitis pigmentosa (age 1), end-stage kidney disease (age 6), and Mainzer-Saldino syndrome (at the time of this study). The proband and her non-consanguineous parents were genotyped by Trio whole exome sequencing, identifying compound heterozygous (paternal and maternal) IFT140 variants in the proband.

GeneAlteration: The proband harbors the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.2176C>G (p.Pro726Ala) variants in trans. The former variant has been shown to mislocalize when exogenously expressed as a cDNA, and is predicted to disrupt a donor splice site (SpliceAI change score of 0.61).

RescueVariant: The variant rescued by CRISPR/Cas9-based gene editing was NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683). This variant was corrected at the same time as a synonymous 3 bp change was introduced to facilitate the detection of the editing event.

RescuedPhenotype: Patient IPSC-derived organoids exhibit Short / clubbed cilia with swollen sips (Figure 3A-3C), Approximately 50% expression of IFT140 at both the mRNA and protein levels (Figures 2D, 2E), and Disturbed apicobasal polarity compromising the ability of iPSC cells to establish polarized spheroids (Figures 5C, 5D).

RescueMethod: CRISPR/Cas9-based gene editing was used to correct one of the proband's two variants (NM_014714.4(IFT140):c.634G>A (p.Gly212Arg), (ClinVar ID: 31683)). A synonymous 3 bp change was simultaneously introduced to facilitate the detection of the editing event.

RescueEvidence: Gene-corrected cells had longer ciliary length with reduced clubbing (Figure 3), approximately twice the expression of IFT140 at the mRNA and protein levels (Figures 2D, 2E), and a higher percentage of polarized spheroids established in organoid culture (indicating recovery of apicobasal polarity).

PMID: 19853238

Gene: BEST1

PMID: 24069149

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (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.

ExperimentName: Morpholino-based knockdown of zbbs1 disrupts ciliary beating pattern.

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of zbbs1, the zebrafish ortholog of human BBS1.

ModelPhenotype: HP:0012262 (Abnormal ciliary motility), HP:0000107 (Renal cyst)

HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)

ModelEvidence: Morpholino-based knockdown of the zbbs1 gene causes hydrocephalus (Figure 3B), formation of pronephritic cysts (Figure 3G), embyronic body axis abnormalities (Figure 4B), heart looping defects (Figure 5B), longer cilia (Figure 7F), and normal ciliary ultrastructure (Figure 7I), and aberrant ciliary motility in the pronephritic tubule and nasal pit (Supplementary Movies).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied the effects of silencing the gene product.

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 166bp from exon 2 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by RT-PCR. Mice were studied at ages 3, 6, and 13 months.

ModelPhenotype: HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT)

HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)

ModelEvidence: Abnormalities of the homozygous Impg2 deletion mice included reduction in the amplitudes of ERG responses from both rods and cones at age 6 months (Figure 2). Pigmentary retinopathy was also observed (Figure 2C), as well as progressive photoreceptor layer loss (Figure 3). Cone markers such as PNA and M-opsin were mislocalized (Figure 4), indicating cone cell disorganization. Enhanced apoptosis was also observed in the photoreceptor cell segments (Figure 5), consistent with the decreased outer nuclei layer thickness.

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.

PMID: 19536307

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#: Bravo-Gil_2016_Proband_95, sex not specified, age 7 years at onset, family origin reported as Spanish

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0000550 (Undetectable electroretinogram), HP:0410280 (Pediatric onset)

CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of simplex retinitis pigmentosa. Night blindness was the first visual symptom.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.

CaseMethod1: next-generation sequencing panel

CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants

CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.

Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1474-2A>G variants in the compound heterozygous state.

ClinVar ID: 12143

CAID: CA381424925

gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1474-2A>G variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1474-2A>G is a canonical splice site variant in intron 14 that is predicted but not confirmed to disrupt BBS1 splicing.

CaseAddInfo: The proband's family has not been described as consanguineous.

CasePMIDs: N/A

PMID: 9855162

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.

PMID: 23189188

ExperimentName: GPR143 silencing in melanoma cells

NonPatientCell: CL:1000458 (melanocyte of skin, specifically the highly pigmented MNT-1 human melanoma cell line)

GeneFunction: GO:1903232 (melanosome assembly)

GeneAlteration: GPR143 silencing was accomplished by transient transfection of MNT-1 cells with specific siRNA, alongside a non-targeting siRNA control.

FunctionalEvidence: siRNA-treated cells exhibited 50% reduction in mature melanosomes and melanin-containing cells by immunofluorescence (Figures 2E, 2F, 2G). This was confirmed by electron microscopy (Figures 2H, 2I, 2J, 2K). GPR143 silencing also resulted in a combination of normal sized melanosomes and enlarged macromelanosome precursors (Figures 2I, S2A). These cellular defects are an approximate match to the giant melanosomes in the melanocytes of the human patients as well as the hypopigmentation of the fundus.

FAVariants: GPR143 disruption was siRNA-based, and patient-associated variants were not studied.

PMID: 30319355

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

ExperimentName: Morpholino-based disruption of Impg2 in medaka fish

NonHumanModel: Oryzias latipes

GeneAlteration: Model animals were subjected to targeted disruption of Impg2 by morpholino-based silencing.

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

HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)

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 Impg2 ortholog using a morpholino.

PMID: 12506099

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.

ExperimentName: Naturally occurring mouse model of Nyx loss-of-function

NonHumanModel: Mus musculus

GeneAlteration: This naturally occurring model, previously known to exhibit the absence of b-wave in ERG recordings, harbors an 85-bp deletion in the final exon of the Nyx gene that shifts the frame and replaces the C-terminal 61% of the protein product with 170 novel amino acids. The predicted effect is loss-of-function.

ModelPhenotype: HP:0007984 (Electronegative electroretinogram), HP:0000649 (Abnormality of visual evoked potentials), HP:0007663 (Reduced visual acuity), HP:0001419 (X-linked recessive inheritance)

HumanPhenotype: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: The model exhibited reduced amplitude of dark-adapted bright flash electroretinogram b-wave (electronegative ERG) but normal amplitude of the a-wave (PMID: 9804152). Visually-driven cortical activity was also abnormal (9804152). Visual acuity was also reduced (Figure 4). Inheritance was X-linked recessive (Figure 3), which also matches the human families.

ModelVariant: The model is naturally occurring, and so the affected animals harbor a variant that does not have an exact human patient equivalent.

PMID: 18179896

Gene: KCNJ13

HGNC: 6259

Disease: snowflake vitreoretinal degeneration

MONDO: 0008663

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of snowflake vitreoretinal degeneration is ~1 in 1,000,000 (https://www.orpha.net/en/disease/detail/91496).

Penetrance: Known disease-causing alleles appear to be completely penetrant (PMID: 14644728).

Case#: Bech-Hansen_2000_Patient_610-1, male, age and race not mentioned, national origin in Costa Rica

CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness)

CaseHPOFreeText: Patients in this study have a diagnosis of complete congenital stationary night blindness. Although this implies nyctalopia and photopic vision loss, specific phenotypic details are absent.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Linkage analysis was performed using 17 X-chromosomal restriction fragment length polymorphism markers.

CaseMethod1: FokI restriction enzyme digestion of the relevant PCR product to monitor segregation in the proband and family members

CaseMethod2: Sanger sequencing of PCR amplified exons from NYX

CaseGenotypingMethod: Linkage analysis was initially performed using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to restriction enzyme analysis of PCR products and Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) variant on the X chromosome.

ClinVar: 11421

gnomAD: NM_001378477.3(NYX):c.1034G>A (p.Trp345Ter) has a maximum allele frequency of 0.00007388 (2/27070, with no males or homozygous females) in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/X-41333755-G-A

VariantEvidence: This nonsense variant is located in the final exon and is not predicted to trigger NMD, but introduces a premature stop codon that truncates 28% of the protein product. The disrupted region is part of the predicted GPI anchor responsible for tethering the protein to the membrane.

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 12118255

Gene: BBS1

HGNC: 966

Disease: Bardet-Biedl syndrome 1

MONDO: 0008854

InheritancePattern: autosomal recessive

Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (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.

ExperimentName: Phenotypic characterization of the heterozygous Timp3Ser179Cys Knock-In Mouse

NonHumanModel: Mus musculus (129/Sv and hybrid C57BL/6 × 129/SvJ background)

GeneAlteration: The mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.

ModelPhenotype: HP:0007703 (Abnormality of retinal pigmentation), Abnormalities of the inner aspect of Bruch's membrane

HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation, PMID:27601084, PMID:16989765), thickening of the inner part of Bruch's membrane

ModelEvidence: While the model system phenotype does not recapitulate all of the human SFD phenotypes, most of which represent the later stages of disease progression, it does recapitulate some early events from the human phenotype, such as abnormalities of Bruch's membrane and the retinal pigment epithelium. The retinal pigment epithelium exhibits structural abnormalities in mutant animals relative to wild-type controls, at both 8 months and 30 months. At 8 months specifically, 15%–20% of RPE areas analyzed showed loss of vertical orientation and increased distances between processes at the cellular bases (Fig. 3) . Patchy thinning of basal microvilli was observed adjacent to Bruch’s membrane, with disrupted packing of microvilli and caverns extending from the basal labyrinth (Figure 3). Timp3 western blots of RPE-choroid ECM extracts from knock-in mice also accumulated higher-molecular weight complexes of Timp3 (Figure 5), similar to the exogenously expressed human variant (PMID:10854443).

ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678). While the article refers to the variant as "Ser156Cys", the updated nomenclature should be Ser179Cys (including the 23-amino acid N-terminal signal peptide).

PMID: 12147610

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

PMID: 22503633

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#: 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_1998_Patient_I-1, male, age and ethnicity not described

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007641 (Dyschromatopsia), HP:0000613 (Photophobia), HP:0000603 (Central scotoma), HP:0011516 (Achromatopsia), HP:0007994 (Peripheral visual field loss), HP:0007675 (Progressive night blindness), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: Onset was during the 1st decade of life. Diagnosis was autosomal dominant cone-rod dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing established linkage to the D17S1796 and D17S1881 microsatellite markers.

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

CaseMethod2: N/A

CaseGenotypingMethod: The proband and his family members were subjected to linkage analysis using the D17S1796 and D17S1881 microsatellite markers, as well as sequencing of PCR products from each of the 18 exons of the GUCY2D locus.

Variant: The proband harbors the NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] variant in the heterozygous state.

ClinVar: 453244

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.3(GUCY2D):c.[2511G>C;2512C>T;2516C>T] is a missense variant that causes three adjacent substitutions at the protein level (p.Glu837Asp;Arg838Cys;Thr839Met), 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: 9618177, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).

CaseAddInfo: The patient is a member of a three-generation family with affected children and grandchildren.

CasePMIDs: N/A

PMID: 9683616

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.

Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.

PMID: 8981947

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: 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#: II.1, F, Age of Onset: 7-8 y.o., Ethnicity: Turkish.

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

CaseHPOFreeText: Proband comes from a consanguineous family.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Exome sequencing.

Variant: NM_021831.6:c.883G>A (p.Asp295Asn).

ClinVar: 242932.

CAID: CA10584033.

gnomAD: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband has two affected siblings. They were evaluated by Sanger sequencing. II.3 had age of onset at 7-8 y.o and was noted to have mixed astigmatism and mental retardation

II.4 had age of onset at 12 y.o and was noted to have

Both siblings were homozygous for the same variant as the proband.

Since targeted analysis of all genes linked to retinal disorders did not reveal a pathogenic mutation in pedigree E, we extended our search to include the entire exomes of the two affected family members. With this approach, a homozygous missense mutation (Asp295Asn) was detected in the deglutamylase gene AGBL5 which was confirmed in all affected family members while the unaffected parents are heterozygous carriers.

CasePMIDs: N/A.

PMID: 15623792

Gene: CRB1

HGNC: 2343

Disease: pigmented paravenous retinochoroidal atrophy

MONDO: 0008246

InheritancePattern: autosomal dominant

Prevalence: Orphanet defines pigmented paravenous retinochoroidal atrophy as a rare disorder with incidence lower than 1 in 1,000,000. However, the incidence is not well-reported in published papers and may be more common than this.

Penetrance: The paper reporting affected family members shows 6 affected genotype-positive individuals and 1 unaffected genotype-negative individual. On the other hand, the high frequency of the variant in gnomAD would be consistent with incomplete penetrance or low rate of diagnosis.

FamilyLabel: McKay_2005_Family, family ethnic origin reported as white

Family#PresentingHPOs: HP:0000533 (Chorioretinal atrophy), HP:0007903 (Paravenous chorioretinal atrophy), HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)

FamilyHPOFreeText: The patient and affected family members have been diagnosed with pigmented paravenous retinochoroidal atrophy. Expressivity is very variable, but all members showed subtle symmetrical chorioretinal atrophy in the inferior quadrant as the presenting feature, with atrophy later becoming more widespread. The proband had optic disc drusen. OCT through an area of bony spicule pigmentation showed that the pigment was located in the superficial neuroretina.

Family#PresentingNotHPOs: HP:0030603 (Abnormal optical coherence tomography)

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Possibly the United Kingdom

Ethnicity: Not mentioned

Race: White

Family#PreviousTesting: Sanger sequencing of candidate genes associated with retinal degeneration was performed, with only the CRB1 locus specifically identified.

Family#Method1: Sanger sequencing of CRB1

Family#Method2: N/A

Family#GenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of candidate genes associated with retinal degeneration, including the CRB1 locus.

Affected: 6

Unaffected: 1

Segregations: Five segregations are reported in the family, with none inconsistent. The pedigree is shown in Figure 1.

PublishedLOD: 1.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: McKay_2005_Family_Proband_III:3

Variant: The affected family members harbor the NM_201253.3(CRB1):c.484G>A (p.Val162Met) variant in the heterozygous state.

ClinVarID: 5738

gnomAD: This variant is found in gnomAD v4.1.1 at a frequency of 0.001610 overall, with a similar frequency in the European (non-Finnish) population and 6 homozygotes overall https://gnomad.broadinstitute.org/variant/chr1-197328835-G-A?dataset=gnomad_r4

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

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

PMID: 15557452

Gene: RPE65

HGNC: 10294

Disease: Retinitis pigmentosa 20

MONDO: 0013425

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 recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.

Penetrance: Fully penetrant, with onset typically in childhood

PMID: 10951519

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.

Penetrance: Fully penetrant, with onset in neonates or in infancy

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

FamilyLabel: Hull_2016_Family_1

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy)

Family#PresentingHPOFreeText: N/A

FamilyNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 2

Unaffected: 0

Segregations: 1 segregation was reported. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Hull_2016_Patient_1.1

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

PMID: 27307694

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: Hull_2016_Family_2

Family#PresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity)

Family#PresentingHPOFreeText: N/A

FamilyNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

Family#PreviousTesting: Variants in REP1 and PRPH2 were initially excluded.

Family#Method1: Candidate gene sequencing

Family#Method2: Bidirectional, targeted Sanger sequencing within the RPE65 locus

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences

Affected: 3

Unaffected: 2

Segregations: 3 segregations were reported. 1 inconsistent segregation was observed, with a genotype-positive individual who did not exhibit phenotypes. The pedigree can be found in Figure 5. The possibility of family consanguinity was not mentioned.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: 1 genotype-positive family member was phenotype-negative, but had an affected child.

ProbandLabel: Hull_2016_Patient_2.1

Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.

ClinVar: 750796

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

FamilyAddInfo: The possibility of family consanguinity was not mentioned.

FamilyPMIDs: N/A

ExperimentName: PDE6A forms a complex with PDE6B and PDE6G

InteractingGene: HGNC:8786 (PDE6B, implicated in retinitis pigmentosa 40) and HGNC:8789 (PDE6G, implicated in retinitis pigmentosa 57)

InteractionType: physical

InteractionMethod: size exclusion chromatography

InteractionEvidence: Purification of the cGMP phosphodiesterase complex from bovine rod outer segments yields a subunit of 88 kDa (PDE6A), a subunit of 84 kDa (PDE6B), and a subunit of 13 kDa (PDE6G), (Figure 2). This article shows that PDE6A interacts with and co-purifies with PDE6B and PDE6G in a single complex isolated from bovine retina. A subsequent article by Pittler et al. later established the position of PDE6A on chromosome 5 (PMID: 2155175).

ExperimentName: Intracellular localization of exogenously expressed wild-type and variant CLN5

NonPatientCell: BKH-21 cells (fibroblast-derived cell line, EFO:0002009)

GeneFunction: Localization to lysosome (GO:0005764)

GeneAlteration: The variant was introduced into the construct encoding CLN5 using site-directed mutagenesis.

FunctionalEvidence: Localization studies were performed in BHK-21 cells transiently transfected with wild-type or variant CLN5. The wild-type co-localized with lysosome and late endosome markers, while the variant co-localized with a Golgi marker (Fig. 3D–F) and showed some ER staining and vesicular-like staining. The stability of the variant following cyclohexamide treatment was also shorter than the wild-type. (Fig. 4G-4H).

FAVariants: The variant used was NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) (ClinVar:2564).

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

PMID: 10953198

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#: 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