GroupName: Tabata_1998_Group

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar)

GroupHPOFreeText: Relatively late onset of phenotypes during the 6th, 7th, or 8th decade of life.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupDemographics

NumberMales: 4

NumberFemales: 5

CountryOrigin: Japan

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: The individuals mentioned range in age from 52 to 75.

TotalNumber: 9

FamilyInfo: 9

NoFamily: 0

VariantCount: 5

NonVariant: 4

OtherVariant: N/A

GroupPreviousTesting: Sanger sequencing of PCR-amplified exon 5

GroupGenotypingMethod: PCR-based heteroduplex analysis using gel electophoresis, as well as SSCP analysis of exon 5.

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.

FamilyLabel: Tabata_1998_Family_Ue

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

FamilyHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (between the ages of 71 and 75).

FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)

FamilyNotHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved.

CountryOrigin: Japan

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

Family#GenotypingMethod: Sanger sequencing

Affected: 3

Unaffected: 0

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Tabata_1998_Family_Ue_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

FamilyLabel: Gliem_2015_Family_3

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

FamilyHPOFreeText: Onset of symptoms in the early fourth or fifth decade of life, with dark adaptation problems being the first symptoms, central and/or midperipheral chorioretinal atrophy, and central fibrosis or focal fibrotic changes, thinning of choroid

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

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

Family#GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes, confirming that the TIMP3 variant co-segregated with the disease.

Affected: 2

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: The number of affected individuals / segregations was insufficient to estimate a LOD score.

ProbandLabel: Gliem_2000_Family_3_patient_III.5

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case: Gliem_2000_Family_2_patient_V.1, male, country of origin Germany, onset at 51 years of age

DiseaseAssertion: Sorsby fundus dystrophy

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

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0012508, (Metamorphopsia), HP:0000662 (Nyctalopia)

CaseHPOFreeText: Presentation at age 51 with visual loss. Evaluation at age 71 found widespread central and midperipheral chorioretinal atrophy, thinning of the choroid in areas of atrophy, central focal subretinal fibrosis at the posterior pole, metamorphopsia (with onset in the sixth decade of life), and nyctalopia that was only developed late in disease progression.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

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

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

SupplementalData: N/A

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

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

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

Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)

CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.

CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Phenotypic characterization only

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

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Proband harbors the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

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

Group Phenotypes

GroupName: Gliem_2015_Group_1

GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia)

GroupHPOFreeText: Central and midperipheral atrophy, Central fibrosis, Dark adaptation problems, Progressive loss of visual acuity

GroupNotHPOs: N/A

GroupDemographics

NumberMales: 7

NumberFemales: 13

CountryOrigin: Germany

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: 52-79 at time of evaluation

TotalNumber: 20

GroupPreviousTesting: N/A

GroupGenotypingMethod Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.

GroupAddInfo: The group consisted of 3 unrelated families.

PMID: 25766588

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

FamilyLabel: Gliem_2015_Family_1

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0030605 (Abnormal indocyanine green angiography), HP:0012508 (Metamorphopsia), HP:0000662 (Nyctalopia), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: Onset in the fifth or sixth decade of life with dark adaptation problems or metamorphopsia, Indocyanine green angiography showing late-phase hypofluorescence early in the disease process, central and midperipheral atrophy, reduced choroidal thickness, yellow deposits in older affected family members, CNV in some patients but not others

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 7

Unaffected: 1

Segregations: 7

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_1_patient_II.1

Variant: Patients harbor the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.

CAID: CA411540328

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

FamilyLabel: Gliem_2015_Family_2

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

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

FamilyNotHPOs: HP:0000662 (Nyctalopia)

FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms

CountryOrigin: Germany

Family#PreviousTesting: N/A

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

Affected: 6

Unaffected: 2

Segregations: 12

PublishedLOD: N/A

eLOD: 2.1

AddSegregationInfo: N/A

ProbandLabel: Gliem_2000_Family_2_patient_V.1

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

CAID: CA411540365

gnomAD: Variant is absent from gnomAD.

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

FamilyPMIDs: PMID:25390527

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540149

gnomAD: Variant is absent from gnomAD.

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

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

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

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

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

GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

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

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

NonPatientCell: ARPE-19 (human retinal pigment epithelial) cell line (CLO:0001749, CL:0009004)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: A TIMP3 expression construct encoding the Glu162Lys variant (referred to in the paper as "Glu139Lys") was generated by PCR-based mutagenesis of the wild-type pCDNA3-TIMP3.

FunctionalEvidence: The TIMP3 variant was exogenously expressed in ARPE-19 cells alongside a mock transfected control (not a wild-type control). Immunoblotting of non-reduced samples detected both monomeric (24 kDa) and dimeric (48 kDa) forms of the variant (Figure 8). Reverse zymographs of extracellular matrix from both wild-type TIMP3- and variant TIMP3-transfected cells revealed the presence of the dimeric species for the variant but not the wild-type, and confirmed its intact metalloproteinase inhibitory activity (Figure 9). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of inheritance.

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

FamilyLabel: Saihan_2009_Family

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000529 (Progressive visual loss), HP:0000572 (Visual loss), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization)

FamilyHPOFreeText: First presenting phenotypes were reduction of night vision and slow dark adaptation (with onset in fifth decade, 1 to 11 years prior to vision loss). Nyctalopia was progressive, with onset in the fifth decade of life (age 45-47). Vision loss was sudden, in some cases bilateral, and occurred in the fifth or sixth decade of life (age 48-56). Drusen-like deposits were present at the posterior pole in all three patients but varied in severity (possibly in proportion to age at examination). The degree of vision loss also varied in severity between patients and between the left and right eyes of each patient. Choroidal neovascularization was hemorrhagic and initiated loss of central vision.

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

FamilyNotHPOFreeText: No history of renal disease or systemic disease was consistently observed among the affected family members.

CountryOrigin: British (of Welsh origin)

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

Family#GenotypingMethod: Mutational screening of TIMP3 by bidirectional Sanger sequencing

Affected: 3

Unaffected: 2

Segregations: 2

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Saihan_2009_Family_patient_III:4

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

CAID: CA411540222

gnomAD: Variant is absent from gnomAD.

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

FamilyPMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Rheumatological exam and renal function were both normal.

CasePreviousTesting: Phenotypic characterization only

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

PreviouslyPublished: PMID:11734514

SupplementalData: N/A

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

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

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

NonPatientCell: COS-7 cells (EFO:0001643, CLO:0002597)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: TIMP3 expression constructs encoding the "Ser181Cys", "Ser156Cys", "Gly166Cys", and "Glu139X" variants (officially referred to as the Ser204Cys, Ser179Cys, Gly189Cys, and Glu162X variants) were generated by PCR-based mutagenesis of the wild-type TIMP-3-pCI.neo construct.

FunctionalEvidence: The TIMP3 variants were exogenously expressed in COS-7 cells alongside the wild-type control. Reverse zymography of extracellular matrix from these cells revealed the presence of dimeric species with metalloproteinase inhibitory activity in the variant-transfected conditions, but not in the wild-type control (Figure 3). These bands were confirmed to be TIMP3 by immunoblotting the extracellular matrix from these cells under non-reducing conditions, as they disappeared under reducing conditions (Figure 4). Under reducing conditions, the variant-transfected cells show higher levels of monomeric TIMP3 relative to the wild-type control (Figure 4b), but it should be noted that the wild-type control is depicted on a separate blot / exposure. The dimerized Glu162X variant is difficult to distinguish from other full-length monomeric species, but appears to be present as well (Figure 5).

FAVariants: Variants used were equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676), NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) (ClinVarID:12678), NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) (ClinVarID:12679), and NM_000362.5(TIMP3):c.484G>T (p.Glu162X) (ClinVarID:12680).

PMID: 10854443

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

FamilyLabel: Langton_2000_Family_1

Family#PresentingHPOs: HP:0031609 (Geographic atrophy), HP:0007663 (Reduced visual acuity), HP:0007703 (Abnormality of retinal pigmentation), HP:0000512 (Abnormal electroretinogram)

FamilyHPOFreeText: First presentation of symptoms was in the 3rd or 4th decade of life. Geographic macular atrophy was the cause of central vision loss. Retinal pigmentary disturbances were peripheral. Scotopic ERGs were abnormal. Other common SFD phenotypes were seen in some affected individuals but not uniformly across all affected family members.

FamilyNotHPOs: N/A

CountryOrigin: British (PMID:11734514)

Family#PreviousTesting: Family previously diagnosed with SFD, with details provided in PMID:11734514.

Family#GenotypingMethod: Sanger sequencing of PCR product from Exon 5 of the TIMP3 gene.

Affected: 3

Unaffected: 2

Segregations: N/A

PublishedLOD: N/A

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Langton_2000_Family_1_patient_II2

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

ClinVar: 12680

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant is referred to in the paper as "Glu139X" but encodes Glu162X in the updated polypeptide sequence (which includes the 23-amino acid N-terminal signal peptide).

FamilyPMIDs: PMID:11734514

PMID: 32666594

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Functional characterization of patient-derived hiPSC-RPE cells

PatientCell: CL:0002586, or retinal pigment epithelial cell (retinal pigmented epithelium generated from patient-derived induced pluripotent stem cells, or hiPSC-RPE)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0051045 (negative regulation of membrane protein ectodomain proteolysis), GO:0016525 (negative regulation of angiogenesis)

GeneAlteration:** Patient cells were heterozygous carriers of the NM_000362.5(TIMP3):c.610A>T p.Ser204Cys variant, or unaffected controls that were homozygous for the non-variant allele.

FunctionalEvidence: hiPSC-RPE cells from SFD patients exhibit altered function relative to equivalent cells from unaffected individuals. They secrete a decreased quantity of TIMP3 (Figure 4C), indicating accumulation and retention of TIMP3 either within the cells or in the associated extracellular matrix. Finally, they express abnormal proteomic profiles with elevated levels of the known TIMP3 binding partner EFEMP1 and the known drusen component apolipoprotein E (Figure 5). The epithelial layer formed by these patient-derived cells exhibits reduced transepithelial electrical resistance (Figure 2C). Other known functions like metalloproteinase inhibition are retained by the variant-harboring cells (Figure 4D). These findings are consistent with a gain-of-function mechanism.

FAVariants: This experiment studied patient cells harboring the NM_000362.5(TIMP3):c.610A>T p.Ser204Cys variant (ClinVarID 12676).

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

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

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

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

CaseNotHPOFreeText: Features of syndromic retinal dystrophy

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

CaseMethod1: Limited genetic testing for 13 candidate genes

CaseMethod2: N/A

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

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

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

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

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

CasePMIDs: N/A

PMID: 32715858

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

FamilyLabel: DeBenedictis_2020_Family_1

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007894 (Hypopigmentation of the fundus)

Family#PresentingHPOFreeText: Onset in 5th decade of life, initial diagnosis not with SFD but with retinitis pigmentosa.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Features of syndromic retinal dystrophy

CountryOrigin: N/A

Ethnicity: Proband has Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side.

Race: Caucasian

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

Family#Method1: Limited genetic testing for 13 candidate genes

Family#Method2: N/A

Family#GenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel

Affected: 2

Unaffected: 0

Segregations: There was 1 segregation reported, while consanguinity was not mentioned. The pedigree was not depicted.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: DiBenedetto_Patient_1

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

CAID: CA411539826

gnomAD: The variant is not found in gnomAD.

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

FamilyPMIDs: N/A

PMID: 7550309

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

FamilyLabel: Jacobson_1995_Family_1

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

FamilyHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring and degeneration.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United States (mentioned in PMID:8981947)

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

Family#GenotypingMethod: PCR amplification of exon 5 in samples from each family member, followed by enzyme digestion with the Bbv1 restriction endonuclease.

Affected: 6

Unaffected: 2

Segregations: 5

PublishedLOD: N/A

eLOD: 1.5

AddSegregationInfo: N/A

ProbandLabel: Jacobson_1995_Family_1_Patient_III-5

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

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA411540415

gnomAD: Variant is absent from gnomAD.

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

FamilyLabel: Weber_1994_Family_M

Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity)

FamilyHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision.

FamilyNotHPOs: N/A

CountryOrigin:

Family#PreviousTesting:

Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

Affected: 1

Unaffected: 1

Segregations: N/A

PublishedLOD:

eLOD: Insufficient information available

AddSegregationInfo: Absence of segregation info from the family is due to the fact that genotyping was limited to only the proband and one unaffected control.

ProbandLabel: Weber_1994_Family_M_patient_IV-2

Variant: NM_003490.4:c.711+5602T>C, p.Tyr191Cys

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Tyr168Cys" but encodes Tyr191Cys in the updated polypeptide sequence.

FamilyPMIDs: PMID:2000899

FamilyLabel: Weber_1994_Family_B

Family#PresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)

FamilyHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.

FamilyNotHPOs: N/A

CountryOrigin: Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

Family#PreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).

Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_B_patient_V-1

Affected: 1

Unaffected: 1

Segregations: N/A

PublishedLOD: A multipoint LOD Score of 7.43 was published for the interval between tandem repeat markers D22S275 and D22S274 on chromosome 22q13, a region that includes the TIMP3 locus (PMID:7920634).

eLOD: Insufficient information available

AddSegregationInfo: N/A

ProbandLabel: Weber_1994_Family_B_patient_V-1

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Ser181Cys" but encodes Ser204Cys in the updated polypeptide sequence. A more detailed pedigree is available from an earlier publication (PMID:7920634), but genotyping was not performed at that time, resulting in a lack of segregation data.

FamilyPMIDs: PMID:2695876, PMID:7920634

Case: Weber_1994_Family_B_Patient_V-1, male, country of origin Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)

CaseHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).

GenotypingMethod: Sanger sequencing

PreviouslyPublished: PMID:2695876, PMID:7920634

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys, which was first referred to in PMID:7894485 as "Ser181Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Ser204Cys in the full/updated polypeptide sequence.

ClinVar: 12676

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

PMID: 7894485

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: Weber_1994_Family_M_Patient_IV-2, male, age 28 at onset of symptoms

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0000819 (Diabetes mellitus), HP:0007703 (Abnormality of retinal pigmentation), HP:0012805 (Iris transillumination defect), HP:0012231 (Exudative retinal detachment), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000603 (Central scotoma), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

CaseHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision. Granularity / abnormalities of the RPE were present in both eyes and preceded the onset of visual problems in the initially-unaffected eye. Serous detachment of sensory retina had underlying pigment epithelial detachment. CNV was accompanied by leakage from foveal avascular zone. Loss of visual acuity was progressive but possibly stabilized by argon green laser photocoagulation treatment.

CaseNOTHPOs: HP:0030584 (Color vision test abnormality), HP:0007957 (Corneal opacity), HP:0000518 (Cataract)

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2

PreviouslyPublished: PMID:2000899

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which was first referred to in PMID:7894485 as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Tyr191Cys in the full/updated polypeptide sequence.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

FamilyLabel: Felbor_1997_Family_1

Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0007703 (Abnormality of retinal pigmentation), HP:0000501 (Glaucoma)

FamilyHPOFreeText: 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 experienced progressive vision loss, iris atrophy, and glaucoma in some cases.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Finland

Family#PreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a mobility shift in exon 5 that was specific to affected individuals. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene, in samples from the proband and a control individual.

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

Affected: 9

Unaffected: 9

Segregations: 8

PublishedLOD: Maximum LOD score, Zmax, was reported as 3.03 (at theta = .001, for the D22S281 marker, previously linked to the TIMP3 locus in PMID:8919688)

eLOD: 2.4

AddSegregationInfo: N/A

ProbandLabel: Felbor_1997_Family_1_patient_III-4

Variant: Affected patients harbor the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.

ClinVar: 12679

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: This highly consanguineous family was previously 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.

FamilyPMIDs: PMID:7148944, PMID:2387082

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.

PMID: 32828705

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Oxidative stress sensitivity in the homozygous Timp3Ser179Cys Knock-In Mouse

NonHumanModel: Mus musculus (C57Bl/6J background)

GeneAlteration: The gene alteration was constructed in a previous paper (PMID:12147610), in which 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:0000580 (Pigmentary retinopathy), HP:0007703 (Abnormality of retinal pigmentation)

HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation)

ModelEvidence: The phenotypes of this model system recapitulate some of the degenerative features of the human model. Sensitivity to oxidative stress was revealed when low-dose sodium iodate triggered RPE degeneration and disorganization in the Timp3 S179C/S179C mice but not the wild-type controls (Figure 4). Rhodamine-phalloidin staining also exhibited an increased area of degeneration in the central region of the RPE in mutant mice but not in the wild-type controls (Figure 5). It is important to point out the caveat that the mice were homozygous for Timp3 Ser179Cys, whereas human patients are heterozygous. This difference in genotype introduces the possibility of loss-of-function effects that are specific to the mouse but absent from the human patients.

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).

GroupName: Naessens_2019_Group

GroupPresentingHPOs: HP:0011510 (Drusen)

GroupHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.

GroupNotHPOs: N/A

GroupNotHPOFreeText: pulmonary involvement

GroupDemographics

NumberMales: 13

NumberFemales: 9

CountryOrigin: Belgium (Families 1 and 3) or northern France (Family 2)

Ethnicity: Not mentioned

Race: Not mentioned

AgeRange: The individuals mentioned range in age from 51 to 74 years, although other unmentioned individuals may be older or younger.

TotalNumber: 22

FamilyInfo: 21

NoFamily: 1

VariantCount: 22

NonVariant: 0

OtherVariant: N/A

GroupPreviousTesting: N/A

GroupGenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

FamilyLabel: Naessens_2019_Family_2

FamilyPresentingHPOs: HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration)

FamilyHPOFreeText: Relatively late onset of phenotypes within the sixth decade of life or later. Drusen / deposits were seen in the younger (57-year old) family member who had not yet developed phenotypes.

**FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Pulmonary involvement

CountryOrigin: France (northern)

Family#PreviousTesting: N/A

Family#GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

Affected: 3

Unaffected: 1

Segregations: 2

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Naessens_2019_Family_2_patient_II:1

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: SNP-based haplotype analysis (Figure 4) of Naessens_2019_Family_2 (this family), Naessens_2019_Family_1, and Naessens_2019_Family_3 (single individual) revealed that all three families inherited this variant as part of a shared region of ~6.4 Mb encompassing the TIMP3 locus. This indicated a founder mutation inherited from a distant but shared common ancestor.

FamilyPMIDs: N/A

FamilyLabel: Naessens_2019_Family_1

FamilyPresentingHPOs: HP:0011510 (Drusen)

FamilyHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.

**FamilyNotHPOs: N/A

FamilyNotHPOFreeText: Pulmonary involvement

CountryOrigin: Belgium

Family#PreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

Family#Method1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

Family#Method2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

Family#GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

Affected: 18

Unaffected: 29

Segregations: 23

PublishedLOD: N/A

eLOD: 6.9

AddSegregationInfo: N/A

ProbandLabel: Naessens_2019_Family_1_patient_IV:31

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: Family was previously genotyped in PMID:10873973, but SSCP analysis of all 5 exons and Sanger sequencing of exon 5 were not sufficient at that time to detect the variant in exon 1.

FamilyPMIDs: PMID:10873973

Case: Naessens_2019_Family_1_Patient_IV:31, female, age of onset 51 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000613 (Photophobia), HP:0000572 (Visual loss)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 51, presenting with photophobia). Drusen was described as widespread around the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).

CaseMethod1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3

CaseMethod2: Sanger sequencing of PCR-amplified exon 5 of TIMP3

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: PMID:10873973

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

Case: Naessens_2019_Family_3_Patient_II:1, male, age of onset 53 years old, country of origin Belgium

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Family member genotypes and phenotypes are not available, but variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0011506 (choroidal neovascularization), HP:0007703 (Abnormality of retinal pigmentation)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as calcified around the vascular arcades. CNV was active. Macular atrophy was patchy. Intraretinal pigment migration was observed from midperiphery towards periphery.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

PMID: 30668888

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: Naessens_2019_Family_2_Patient_II:1, female, age of onset 53 years old, country of origin France (northern)

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.

CasePresentingHPOs: HP:0011510 (Drusen), , HP:0000572 (Visual loss), HP:0007401 (Macular atrophy), HP:0007769 (Peripheral retinal degeneration), HP:0011506 (Choroidal neovascularization), HP:0007777 (Chorioretinal scar)

CaseHPOFreeText: Relatively late onset of phenotypes (at age 53, presenting with nyctalopia). Drusen was described as widespread and partially calcified. Macular atrophy was patchy, with round atrophic patches outside the vascular arcades.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Pulmonary involvement

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.

Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.

PMID: 8634721

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_1995_Family_1_patient_1, gender and age not specified, German-Czech family origin

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

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

FamilyLabel: Felbor_1995_Family_1

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is described as German-Czech.

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

Family#GenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.

Affected: 2 (Sanger sequenced)

Unaffected: 1 (Sanger sequenced)

Segregations: N/A

PublishedLOD: Maximum two-point LOD score of 4.75 was reported for marker D22S280 at a recombination fraction of 0.001. D22S280 is also tightly associated with the TIMP3 locus.

eLOD: Insufficient information available

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

ProbandLabel: Felbor_1995_Family_1_patient_1

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

ClinVar: 12678

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: 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.

PMID: 9006347

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: 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

FamilyLabel: Meunier_2016_Family_1

Family#PresentingHPOs: HP:0002097 (Emphysema), HP:0011510 (Drusen), HP:0011506 (Choroidal neovascularization), HP:0000529 (Progressive visual loss), HP:0032342 (Reduced forced expiratory volume in one second), HP:0033663 (Air trapping), HP:0033542 (Bronchial wall thickening), HP:0002110 (Bronchiectasis)

FamilyHPOFreeText: Early onset of abnormality in Bruch's membrane thickness. Drusen and choroidal neovascularization occurred between ages 23 and 40 (early onset) and were bilateral. Legal blindness was observed in almost all patients, although anti-VEGF treatment (bevacizumab) administration in one patient was associated with retained eye function. Pulmonary disease (severe emphysema) was late-onset. Patients in the 6th to 8th decades of life showed air trapping on CT scan, had reduced airflow (FEV1) by 28% to 73%, and bronchial abnormalities. Air trapping and hypoxia were detectable as early as the second decade of life and progressed to more severe pulmonary issues in older family members.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002099 (Asthma)

FamilyNotHPOFreeText: No history of smoking

CountryOrigin: Family origin was not reported.

Family#PreviousTesting: Clinical exams to detail features of affected family members.

Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.

Affected: 7

Unaffected: 2

Segregations: 6

PublishedLOD: N/A

eLOD: 1.8

AddSegregationInfo: N/A

ProbandLabel: Meunier_2016_Family_1_patient_III-1

Variant: NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys is a missense variant predicted to introduce a new cysteine-encoding codon into exon 5.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: While the family has not been previously described, the same variant has been published in PMID:7894485 (without reporting pulmonary symptoms).

PMID: 27601084

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

FamilyLabel: Meunier_2016_Family_2

Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0030506 (Yellow/white lesions of the retina), HP:0011510 (Drusen), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0011506 (Choroidal neovascularization), HP:0007401 (Macular atrophy), HP:0007703 (Abnormality of retinal pigmentation), Bronchial wall thickening HP:0033542

FamilyHPOFreeText: Both eye and lung disease presented at later ages within members of this family. Eye disease onset occurred in the fifth decade of life with nyctalopia as the first presenting phenotype, and drusen / yellow lesions detectable at the posterior pole and in the peripheral retina. Choroidal neovascularization occurred during the 5th and 6th decades of life and led to progressive loss of vision in both eyes. Macular atrophy and retinal pigment abnormalities were also late presenting phenotypes. In addition to bronchial wall thickening, mild cylindrical bronchiectasis and asthma were each observed in one affected family member. Pulmonary symptoms were late in onset and only detected by CT imaging.

FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002097 (Emphysema),

FamilyNotHPOFreeText: No history of smoking

CountryOrigin: Family origin was not reported.

Family#PreviousTesting: Clinical exams to detail features of affected family members.

Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.

Affected: 4

Unaffected: 3

Segregations: 3

**PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: Insufficient number of segregations to estimate LOD score.

ProbandLabel: Meunier_2016_Family_2_patient_III-2

Variant: NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys) is a missense variant predicted to introduce a new cysteine-encoding codon into exon 1. Interestingly, it differs from most other published missense variants in that it affects a codon within exon 1 rather than exon 5.

ClinVar: 843268

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: Family has not been previously described but the same variant has been published in PMID:23023527, PMID:26493035, and PMID:30668888 (without reporting pulmonary symptoms in either study).

PMID: 9642234

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

NonPatientCell: COS-7 cells (EFO:0001643, CLO:0002597)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: A TIMP3 expression construct encoding the "Ser181Cys" variant (more accurately referred to as a Ser204Cys variant) was generated by PCR using a 3' primer that contained the desired substitution.

FunctionalEvidence: The TIMP3 variant was exogenously expressed in COS-7 cells alongside a mock transfected control (not a wild-type control). Reverse zymography of extracellular matrix from these cells revealed the presence of both a monomeric and a dimeric species with metalloproteinase inhibitory activity (Figure 4). This was confirmed by immunoblotting to be TIMP3, and the dimeric species appeared under non-reducing conditions but disappeared under reducing conditions (Figure 5). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of its inheritance. The wild-type control was absent from this figure. It is not clear whether a separate but similar figure showing the wild-type control was performed under reducing or non-reducing conditions.

FAVariants: Variant used was equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676). The variant is referred to in this publication as "Ser181Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Ser204Cys in the full/updated polypeptide sequence.

ExperimentName: Phenotypic characterization of the homozygous Timp3-/- Knock-Out Mouse

NonHumanModel: Mus musculus (C57/Bl6 or CD1 background)

GeneAlteration: A neomycin resistance expression cassette was cloned into plasmid-borne exon 3 of mouse Timp3. The linearized construct was transfected into embryonic stem cells and injected into blastocysts. Animals that had undergone homologous recombination were identified by locus-specific genomic PCR reactions. Predicted loss of Timp3 due to a premature stop codon and nonfunctional mRNA was confirmed at the protein level.

ModelPhenotype: HP:0030605 (Abnormal indocyanine green angiography), HP:0025568 (Abnormal morphology of the choroidal vasculature), HP:0030979 (Dilatation of large choroidal vessels)

HumanPhenotype: HP:0011506 (Choroidal neovascularization)

ModelEvidence: The model showed dilatation of the large choroid vessels, which appeared large and hyperfluorescent during ICG angiography, with balloon-like spots (Figure 3A-3B). While wild-type controls exhibited normal choroidal blood vessel network, Timp3-/- animals had abnormal vessel formations that were strongly dilated or fused (Figures 3C-3H). During in situ zymography, higher local fluorescence intensity indicated increased MMP2 and MMP9 activity in the knockout animals, as expected. Aortic explants from knockout mice showed higher spontaneous microvessel outgrowth than their counterparts from wild-type mice (Figure 6). Rescue assays suggest that the antiangiogenic activity requires the C-terminal region of TIMP3 (Figure 7).

ModelVariant: N/A (Timp3 knockout)

PMID: 18408187

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

PMID: 27587748

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: 31757977

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: 11734514

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: 23023527

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

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0008191 (metalloendoproteinase inhibitor activity)

FunctionalEvidence: The functional evidence consists of an electrophoretic assay in which the 21-kDa chicken ortholog of human TIMP3 shows inhibitory activity towards a metalloproteinase.

FunctionalHPO: Abnormal extracellular matrix turnover in the inner aspect of Bruch's membrane

PhenotypeEvidence: This metalloproteinase inhibitor activity and ECM localization of the gene product indicate that it functions in ECM remodeling, balancing the activity of matrix metalloproteinases. This is consistent with the disease phenotype of abnormal thickening of the inner aspect of Bruch's membrane (PMID:11879143). The inhibitor evidence is shown in Figure 2B, where a 21-kDa band protects a gelatin substrate from enzymatic metalloproteinase activity. The purification of the gene product from the extracellular matrix is depicted in Figure 1. A later study showed that the human ortholog of this chicken gene is the TIMP3 gene, mapped to the region on chromosome 22 between q12.1-q13.2 (PMID:8188246).

PMID: 1845973

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: 16989765

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

FamilyLabel: Lin_2006_Family_1

Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0011510 (Drusen), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000662 (Nyctalopia), HP:0007850 (Retinal vascular proliferation)

FamilyHPOFreeText: Disease onset was between the fifth and seventh decades of life. Mild nyctalopia preceded choroidal neovascularization by one or more decades in most individuals. Drusen, RPE atrophy, thickening of Bruch's membrane, and blockage of normal central choroidal fluorescence were also early stage disease phenotypes that preceded choroidal neovascularization. Choroidal neovascularization was bilateral in 4 out of 7 affected family members.

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Family reported to have Eastern European Jewish ancestry.

Family#PreviousTesting: Complete ophthalmological exam to define clinical features of affected family members.

Family#GenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5, for 7 affected and 2 unaffected family members.

Affected: 7

Unaffected: 1

Segregations: 13

PublishedLOD: N/A

eLOD: 3.9

AddSegregationInfo: N/A

ProbandLabel: Lin_2006_Family_1_patient_IV-8

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

FamilyAddInfo: N/A

FamilyPMIDs: N/A

Case: Lin_2006_Family_1_patient_IV-8, female, 62 years of age at presentation, Eastern European Jewish ancestry

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0012508 (Metamorphopsia), HP:0011510 (Drusen), HP:0025148 (Dark choroid), HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0000662 (Nyctalopia), HP:0007703 (Abnormality of retinal pigmentation),

CaseHPOFreeText: Patient presented with central visual field loss and metamorphopsia in one eye, 10 years after a normal results from fundus and vision exam. Fluorescein angiography of the other eye revealed drusen and dark choroid. Choroidal neovascularization progressed to a central disc-shaped scar despite several treatments with argon laser thermal photocoagulation. The less affected eye initially showed mild nyctalopia only, but progressed within 2 years to fibrovascular pigment epithelial detachment, circular blocking lesion, choroidal neovascularization, and visual acuity loss.

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: Complete ophthalmological exam to define clinical features.

CaseGenotypingMethod: Bidirectional Sanger sequencing of PCR products from exons 1 through 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: NM_000362.5(TIMP3):c.542A>G, p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution).

CAID: CA411540357

gnomAD: Variant is absent from gnomAD.

VariantEvidence: p.His181Arg is a missense variant predicted to replace a conserved histidine residue in exon 5 with arginine (conservative substitution). Molecular modeling predicts that the affected amino acid is located on a protein-protein interaction interface.

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0016525 (negative regulation of angiogenesis)

FunctionalEvidence: The previously known ability of TIMP3 protein to block the binding of VEGF to the VEGFR-2 receptor (PMID:12652295, PMID:19478078) is mapped to the C-terminal region of TIMP3 consisting of amino acids 160-211 (Figures 1c, 2b). This region is relevant to disease in that nonsense variants (PMID:10854443) and splice site disrupting variants (PMID:9760202) of TIMP3 are predicted to remove most or all of this domain. This region is not only necessary and sufficient to block VEGF binding to VEGFR-2 in ELISA assays (Figure 2b), but also can block VEGF-stimulated endothelial migration (Figure 4) and proliferation (Figure 6). In an animal model of choroidal neovascularization (CNV) with lesions induced by laser, the injection of C-terminal TIMP3 peptides can limit CNV-based lesion size (Figure 7). This introduces the possibility that some phenotypes of Sorsby fundus dystrophy such as CNV may be mediated by loss of normal TIMP3 function rather than gain of an abnormal TIMP3 function.

FunctionalHPO: HP:0011506 (Choroidal neovascularization)

PMID: 23469166

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

Selection B Expression altered in patients

ExperimentName: Immunohistochemical localization of TIMP3 expression in eye sections from SFD and unaffected human patients

TissueExpression: In both unaffected and SFD patient tissues, strong TIMP3 expression was observed in Bruch's membrane (UBERON:0003957) and associated drusen (Figure 1).

ExpressionEvidence: As previously published (PMID:9006347), strong TIMP3 expression was observed in Bruch's membrane and drusen in both normal and SFD samples (Figure 1). In SFD patient tissues, thickened Bruch's membrane stained positively for TIMP3 as well, but only in areas where the retinal pigment epithelial cells were still intact (not in areas exhibiting RPE loss). Numerous extracellular deposits that stained positively with Periodic acid-Schiff (presumably drusen) were also TIMP3-positive. In some areas, retinal blood vessels were occluded by TIMP3-positive deposits as well. These findings clearly localize TIMP3 to the sites closely associated with pathogenesis within the SFD retina. Interestingly, SFD-like deposits in retinitis pigmentosa tissues were similarly TIMP3-positive (Figure 2).

PMID: 9924344

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_1996_Patient_G, female, age 33 at onset of symptoms, country of origin Austria

DiseaseAssertion: Sorsby's fundus dystrophy

FamilyInfo:

CasePresentingHPOs: HP:0025582 (Submacular hemorrhage), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0007722 (Retinal pigment epithelial atrophy), HP:0030491 (Choriocapillaris atrophy), HP:0011510 (Drusen), HP:0000603 (Central scotoma), HP:0011506 (Choroidal neovascularization), HP:0012231 (Exudative retinal detachment), HP:0000512 (Abnormal electroretinogram)

CaseHPOFreeText: N/A

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: Normal rod and cone signals

CasePreviousTesting: N/A

GenotypingMethod: SSCP analysis detecting mobility shift in exon 5 PCR product, followed by Sanger sequencing of exon 5.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which is referred to in the paper as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence). The corrected variant is p.Tyr191Cys in the full/updated polypeptide sequence.

ClinVar: 12677

gnomAD: Variant is absent from gnomAD.

VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.

PMID: 8728699

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

NonPatientCell*: ARPE-19 (human retinal pigment epithelial) cell line (CLO:0001749, CL:0009004)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: TIMP3 expression constructs encoding the "Ser181Cys", "Ser156Cys", and "Glu139X" variants (officially referred to as the Ser204Cys, Ser179Cys, and Glu162X variants) were generated by PCR-based mutagenesis of the wild-type TIMP-3-pCI.neo construct (previously described in PMID:10854443).

FunctionalEvidence: TIMP3 variants were exogenously expressed in ARPE-19 cells alongside wild-type and empty vector controls. The percentage of exogenously expressed wild-type TIMP3 protein remaining associated with the extracellular matrix after separation of transfected cells from ECM was 20% (after 1 day) or <1% (after 4 days). All three variants were turned over at a slower rate, with 35-50% remaining after 1 day, and 20-25% remaining after 4 days (Figure 2). On the other hand, while the Ser179Cys and Glu162X variants showed reduced ability to inhibit cell surface activation of Pro-MMP2, Ser204Cys did not (Figure 3). As a result, the key, consistent function of TIMP3 variants in SFD may be (toxic) aggregation rather than loss of inhibitory activity.

FAVariants: Variants used were equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676), NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) (ClinVarID:12678), and NM_000362.5(TIMP3):c.484G>T (p.Glu162X) (ClinVarID:12680).

PMID: 16223891

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: 11827795

Gene: TIMP3

HGNC: 11822

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

MONDO: 0007640

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Functional testing of Ser179Cys, Gly190Cys, Tyr191Cys and Ser204Cys variants of TIMP3 in baby hamster kidney (BHK) cells

NonPatientCell: Baby hamster kidney (BHK) cells, EFO:0001643 (kidney-derived cell line), CLO:0000696 (immortal hamster kidney-derived cell line), CLO:0001965 (BHK-21 cell line)

GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)

GeneAlteration: TIMP3 expression constructs encoding the Ser179Cys, Gly190Cys, Tyr191Cys, and Ser204Cys variants (referred to in the paper as "Ser156Cys", "Gly167Cys", "Tyr166Cys", and "Ser181Cys") were generated by PCR-based mutagenesis of wild-type TIMP3 and cloned into the pNUT expression vector.

FunctionalEvidence: BHK cells were stably transfected with each of four variants or wild-type TIMP3. All variants expressed and localized successfully to the extracellular matrix (western blotting), Both variants tested exhibited intact metalloproteinase inhibitor activity in ECM fractions (reverse zymography). All four of the variants accumulated as higher molecular weight species (Figure 1A, Figure 2), with Ser179Cys and Ser204Cys in particular accumulating to a much greater degree than the other variants or the wild-type control (Figure 2). Cell morphology and adherence were affected within the variant-expressing cells. While wild-type-transfected cells were more adherent to the ECM than the untransfected controls were, both variant-transfected cells (Ser179Cys, Ser204Cys) were even more ECM-adherent (Figure 5). Association constants were measured for TIMP3 interaction with a series of metalloproteinases, calculating their values for wild-type TIMP3 and for the Ser156Cys variant, which exhibited a 2- or 3-fold loss of reduction, depending on the substrate (Table 2).

FAVariants: The four variants used were NM_000362.5(TIMP3):c.536C>G, p.Ser179Cys (ClinVar:12678), NM_000362.5(TIMP3):c.568G>T, p.Gly190Cys (CA411540415), NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys (ClinVar:12677), and NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys (ClinVar:12676).

PMID: 15824229

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: 25390527

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: 11879143

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: 9400791

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: 8919688

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