PMID: 15908424

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

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

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

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

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

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

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

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

CasePreviousTesting: PCR-based heteroduplex analysis using gel electophoresis

CaseGenotypingMethod: Sanger sequencing

PreviouslyPublished: N/A

SupplementalData: N/A

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

CAID: CA1139771334

gnomAD: Variant is absent from gnomAD.

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

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

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

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

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

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

CaseMethod1: Homozygosity mapping

CaseMethod2: Sanger sequencing of CABP4

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

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

ClinVar ID: 190959

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

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

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

CasePMIDs: N/A

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

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

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0000545 (Myopia), HP:0000550 (Undetectable electroretinogram), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.887+430_908+274del variant in the homozygous state.

ClinVar: 3547

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

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

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

CasePMIDs: PMID: 20673862

PMID: 36342076

2 patients (fetuses) with recurrent autosomal dominant RBP4 variant

PMID: 19409519

Gene: ADAM9

HGNC: 216

Disease: cone-rod dystrophy 9

MONDO: MONDO:0013002

InheritancePattern: autosomal recessive

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

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

PMID: 11427722

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

PMID: 9683616

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

ExperimentName: Prph2 interacts with Rom1

InteractingGene: ROM1 (HGNC:10254)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of endogenous Prph2 from mouse retinal extracts pulled down Rom1, and vice versa (Fig. 6C).

PMID: 9662406

Gene: CLN5

HGNC: 2076

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

MONDO: 0009745

InheritancePattern: Autosomal Recessive

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

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

PMID: 12160730

Gene: RPGR

HGNC: 10295

Disease: RPGR-related retinopathy

MONDO: MONDO:0100437

InheritancePattern: X-linked

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

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

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

ClinVar: 2137179

CAID: CA224268235

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

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

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) and NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variants in IFT140.

ClinVar: 31683, 31684

gnomAD: The NM_014714.4(IFT140):c.634G>A (p.Gly212Arg) variant is present in gnomAD at a frequency of 0.00009295 in the European (non-Finnish) population (12/129100, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1642177-C-T The NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) variant is present in gnomAD at a frequency of 0.0001210 in the African / African-American population (3/24790, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1570005-G-GC

VariantEvidence: Exogenous expression of the FLAG-tagged p.Gly212Arg variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells that is less severe than one of the other suspected pathogenic missense variants (Figure 3A). NM_014714.4(IFT140):c.3916dup (p.Ala1306fs) is a frameshift variant that introduces a premature stop codon in exon 28/31 and is predicted to trigger NMD or at least to truncate ~11% of the protein product.

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

CasePMIDs: N/A

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

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

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

CaseNotHPOs: HP:0004322 (Short stature), HP:0000765 (Abnormal thorax morphology), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology), HP:0003272 (Abnormal hip bone morphology)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)

CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140

CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140

Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.

ClinVar: 31679

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

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

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

CasePMIDs: N/A

Case#: Perrault_2000_Family_3_Proband, Female, age unknown, family origin in Tunisia with Jewish Sefardi ancestry

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: Single strand conformational polymorphism analysis

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

Variant: The individual is homozygous for the NM_000180.4:c.389del (p.Pro130LeufsTer36) variant.

ClinVar: 98602

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

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

CaseAddInfo: The family is reportedly consanguineous.

CasePMIDs: PMID: 7581387, PMID: 8641699

FamilyLabel: Perrault_2000_Family_11

Family#PresentingHPOs: N/A

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

FamilyNotHPOs: N/A

CountryOrigin: Algeria

Ethnicity: Arab

Race: Not described

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

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

Family#Method2: N/A

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

Affected: 4

Unaffected: 0

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

PublishedLOD: N/A

eLOD: 1.81

AddSegregationInfo: N/A

ProbandLabel: Perrault_2000_Family_11_Proband

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

ClinVar: 9350

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

FamilyAddInfo: N/A

FamilyPMIDs: PMID: 7581387, PMID: 8641699

PMID: 20055437

PMID: 10430891

Gene: GUCY2D

HGNC: 4689

Disease: Cone-rod dystrophy 6

MONDO: 0011143

InheritancePattern: Autosomal Dominant

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

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

Case#: Family_9073_Proband_III-1, onset before age 7 years, male, seen at a medical center in Guangzhou

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

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

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

CaseNotHPOFreeText: N/A

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

CaseMethod1: targeted exome or whole exome sequencing

CaseMethod2: Sanger sequencing of OPN1LW

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

Variant: The individual harbors the NM_020061.6:c.757C>T (p.Gln253Ter) variant in the hemizygous state.

CAID: CA415307744

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

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

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

CasePMIDs: N/A

PMID: 11071390

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.

PMID: 11786058

Gene: RPE65

HGNC: 10294

Disease: Leber congenital amaurosis 2

MONDO: 0008765

InheritancePattern: Autosomal Recessive

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

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

PMID: 11336703

Gene: LRP5

HGNC: 6697

Disease: osteoporosis-pseudoglioma syndrome

MONDO: 0009820

InheritancePattern: autosomal recessive

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

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

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

DiseaseAssertion: Sorsby's fundus dystrophy

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

CasePresentingHPOs: N/A

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

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

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

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

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

SupplementalData: N/A

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

ClinVar: 12679

gnomAD: Variant is absent from gnomAD.

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

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

ClinVar: 40291, 40292

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

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

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

CasePMIDs: N/A

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0047555 (3',5'-cyclic-GMP phosphodiesterase activity)

FunctionalEvidence: Purified PDE6A fusion protein tagged with EGFP and fused with sequences from PDE6C catalyzes cGMP hydrolysis comparably to the known phosphodiesterase enzymes PDE6B and PDE6C (Fig. 4), confirming that PDE6a is a rod-associated phosphodiesterase that hydrolyzes cGMP.

FunctionalHPO: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

PMID: 26188004

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

ExperimentName: Exogenous expression of the RPE65 D477G variant in HEK293-F cells

NonPatientCell: HEK293-F cell line (EFO:0001182)

GeneFunction: all-trans-retinyl-ester hydrolase, 11-cis retinol forming activity (GO:0052885)

GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was introduced by site-directed mutagenesis into canine RPE65 and transiently transfected into HEK293-F cells.

FunctionalEvidence: The variant triggered a moderate decrease in retinoid isomerase activity / 11-cis retinol formation that appeared to be balanced out by the presence of the wild-type allele, rather than acting in a dominant negative fashion (Figure 1B). This loss of function was less dramatic than other hypomorphs known to be associated with autosomal recessive RPE65 retinopathy. Thus, loss of enzymatic function is unlikely to be the primary mechanism by which the variant contributes to autosomal dominantly inherited disease.

FAVariants: NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796)

PMID: 12397430

Gene: NYX

HGNC: 8082

Disease: Congenital stationary night blindness 1A

MONDO: 0010690

InheritancePattern: X-linked recessive

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

Penetrance: Penetrance is thought to be complete.

Case#: Holmberg_Patient_3, male, age 3 at onset and age 19 at time of death, Finnish origin

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

CaseHPOFreeText: Age of onset was 4, while mental decline, visual deterioration and abolished ERG were found at age 6. Giant flash visual evoked potentials were present at age 8, and ataxia at age 9. Seizures and Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: N/A

CaseMethod2: N/A

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

Variant: The patient is homozygous for the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant.

ClinVar: 2564 (homozygous)

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C

VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 10953198

Gene: CLN5

HGNC: 2076

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

MONDO: 0009745

InheritancePattern: Autosomal Recessive

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

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

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

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000662 (Nyctalopia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to clinical phenotyping.

CaseMethod1: Sanger sequencing of PCR products from all exons and flanking regions of the GUCY2D locus

CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13

CaseGenotypingMethod: The proband and her family members were subjected to additional genotyping through restriction fragment length polymorphism analysis, then confirmation by HhaI restriction endonuclease digestion of PCR products from the relevant exon 13.

Variant: The proband harbors the NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) variant in the heterozygous state.

ClinVar: 811743

gnomAD: The variant was not found in gnomAD.

VariantEvidence: NM_000180.4(GUCY2D):c.2513G>C (p.Arg838Pro) is a missense variant located within the coiled-coil domain that mediates dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565).

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

CasePMIDs: N/A

FamilyLabel: Bowne_2011_Family_TCD-H

Family#PresentingHPOs: N/A

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

FamilyNotHPOs: N/A

CountryOrigin: Ireland

Ethnicity: Not mentioned

Race: Not mentioned

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

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

Family#Method2: Candidate gene sequencing

Family#GenotypingMethod: Sanger sequencing of the RPE65 locus

Affected: 3

Unaffected: N/A

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

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

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Bowne_2011_Family_TCD-H_Patient_01

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

ClinVar: 750796

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

FamilyAddInfo: N/A

FamilyPMIDs: N/A

ExperimentName: Conditional Kcnj13 knockout in mice

NonHumanModel: Mus musculus

GeneAlteration: Conditional knockout was generated by inserting a cassette into exon 2 of 3 in the presence of Cre driven by the VMD2 (RPE-specific) promoter.

ModelPhenotype: Photoreceptor layer loss on macular OCT HP:0030609, Retinal degeneration HP:0000546, Abnormality of retinal pigmentation HP:0007703, Attenuation of retinal blood vessels HP:0007843, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

HumanPhenotype: Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:00011, Infantile onset HP:0003593, Strabismus HP:0000486, Nystagmus HP:0000639, Progressive night blindness HP:0007675, Moderate myopia HP:0031624, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Presenile cataracts HP:0007819, Nummular pigmentation of the fundus HP:0030505, Retinal pigment epithelial loss on macular OCT HP:0030611

ModelEvidence: The 6-month-old mouse with induced Cre recombinase shows loss of photoreceptor cell layers (Figure 4F) and severe retinal degeneration (Figure 4G) relative to the control lacking Cre (Figure 4E), but with relative preservation of retinal morphology near the optic nerve. The RPE layer in the Cre-positive knockout cells shows irregular and flattened cell shapes with abnormal nuclear and cytoskeletal morphology relative to the control (Figure 5D). The knockout mouse fundus shows distinct inclusions, especially in the outer segment, as well as some attenuation of retinal blood vessels (Figure 6). ERG a-waves and b-waves are also extinguished (Figure 7A), consistent with loss of the entire photoreceptor layer (Figures 4F, 5B). There was also low amplitude of c-waves originating from the RPE cells (Figure 7C) that could be restored by lentiviral transduction of the functional KCNJ13 gene (Figures 7C, 7D).

ModelVariant: The model features knockout of the endogenous mouse Kcnj13 rather than knock-in of a mutation equivalent to a variant from a human patient.

PMID: 20333770

Gene: EYS

HGNC: 21555

Disease: Retinitis pigmentosa 25

MONDO: MONDO:0011272

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.

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

PMID: 8485575

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

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

CasePresentingHPOs: Abnormal optic disc morphology HP:0012795, Abnormal morphology of the choroidal vasculature HP:0025568, Abnormal light-adapted electroretinogram HP:0008275, Protanopia HP:0011522

CaseHPOFreeText: The proband has a diagnosis of early onset high myopia, yet also shows protanopia. He exhibits myopic fundus changes, with temporal crescent of optic nerve head and tigroid appearance of posterior retina. Rod ERG responses are normal, while cone responses are mildly to moderately reduced.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genotyping of the proband was performed by PCR / RFLP-based analysis of OPN1LW and OPN1MW locus structure, real-time PCR-based analysis of OPN1LW and OPN1MW copy number, and Sanger sequencing of long-range PCR products from exon 3 of OPN1LW and OPN1MW.

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

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

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

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

ClinVarID / CAID: CA2695237719 / 403267

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

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

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

CasePMIDs: PMID: 27339364

PMID: 8641699

Gene: GUCY2D

HGNC: 4689

Disease: Leber congenital amaurosis 1

MONDO: 0008764

InheritancePattern: Autosomal Recessive

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

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

ExperimentName: The Nr2e3rd7/rd7 mouse has aberrant proliferation of mitotic progenitors caused by aberrant expression of rod-specific and cone-specific genes such as blue opsin, resulting from failure to suppress the cone generation program and resulting aberrant expression of rod-specific and cone-specific genes.

NonHumanModel: Mus musculus

GeneAlteration: The Rd7 mouse model has been previously described in PMID: 10805811 and PMID: 11487564, and harbors a large out-of-frame deletion within the Nr2e3 locus in the homozygous state.

ModelPhenotype: Abnormal retinal morphology on macular (whorls and rosettes in outer nuclear layer) OCT HP:0030612, Retinal degeneration (late onset) HP:0000546, Retinal thinning HP:0030329

HumanPhenotype: Retinal degeneration HP:0000546, Sensory hypersensitivity (enhanced blue cone sensitivity) HP:5200058

ModelEvidence: The model has been previously published and exhibits ~30x enhanced blue cone sensitivity (PMID: 11487564), retinal spotting throughout the fundus including whorls in the outer nuclear layer (PMID: 11487564), and late onset retinal degeneration characterized by non-apoptotic cell death reduction of outer nuclear layer thickness (PMID: 34561487), and over-proliferation of ectopic retinal progenitors (PMID: 17266784), as well as increased expression of cone-associated genes (Figure 1).

ModelVariant: The model harbors a deletion of 380bp spanning intronic and coding regions, rather than a specific variant from a human patient.

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

NonHumanModel: Mus musculus

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

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

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

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

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

PMID: 16723661

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

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

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

PMID: 16960802

Gene: CABP4

HGNC: 1386

Disease: cone-rod synaptic disorder, congenital nonprogressive

MONDO: 0012490

InheritancePattern: autosomal recessive

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

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

ExperimentName: RP1L1 physical interaction with RP1

InteractingGene: HGNC:10263 (RP1)

InteractionType: Physical interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of Rp1 or Rp1l1 from transfected 293T cells successfully led to co-immunoprecipitation of the other, indicating their presence in a complex (Figure 7).

FamilyLabel: McKay_2005_Family, family ethnic origin reported as white

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

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

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

Family#PresentingNotHPOFreeText: N/A

CountryOrigin: Possibly the United Kingdom

Ethnicity: Not mentioned

Race: White

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

Family#Method1: Sanger sequencing of CRB1

Family#Method2: N/A

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

Affected: 6

Unaffected: 1

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

PublishedLOD: 1.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: McKay_2005_Family_Proband_III:3

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

ClinVarID: 5738

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

FamilyAddInfo: The family has not been reported as consanguineous.

FamilyPMIDs: N/A

FamilyLabel: Hull_2016_Family_2

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

Family#PresentingHPOFreeText: N/A

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

CountryOrigin: Irish ancestry

Ethnicity: Not mentioned

Race: Not mentioned

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

Family#Method1: Candidate gene sequencing

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

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

Affected: 3

Unaffected: 2

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

PublishedLOD: N/A

eLOD: N/A

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

ProbandLabel: Hull_2016_Patient_2.1

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

ClinVar: 750796

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

FamilyAddInfo: The possibility of family consanguinity was not mentioned.

FamilyPMIDs: N/A

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

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

CaseHPOFreeText: The proband has been diagnosed with pattern dystrophy of the retina/macula. All affected family members including the proband exhibited perifoveal yellow pigment deposits at the level of the RPE.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in this family is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes.

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

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

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

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

ClinVar ID: 13174

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

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

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

CasePMIDs: PMID: 8004111

PMID: 11297544

Gene: PRPH2

HGNC: 9942

Disease: retinitis pigmentosa 7

MONDO: 0011974

InheritancePattern: semi-dominant

Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).

Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).

CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.

CaseMethod2: N/A

CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.

Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.

ClinVar: 98563

gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T

VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.

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

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

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

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

ClinVarID: 5529

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

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

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

CasePMIDs: N/A

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

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

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

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: Whole-genome linkage analysis and haplotype analysis

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

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

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

CAID: CA361692783

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

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

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

CasePMIDs: N/A

PMID: 9328476

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

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

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

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

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

CaseHPOFreeText: The proband has been previously diagnosed with achromatopsia.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: The patient was previously genotyped by Sanger sequencing of CNGB3, CNGA3, and GNAT2.

CaseMethod1: next-generation sequencing of PDE6C and possibly other loci

CaseMethod2: screening of the 22 exons and flanking regions of PDE6C (the only strong candidate gene) using Sanger sequencing

CaseGenotypingMethod: The proband has been genotyped by Sanger sequencing of CNGB3, CNGA3, GNAT2, and PDE6C, as well as next-generation sequencing of PDE6C and possibly other loci.

Variant: The proband harbors the NM_006204.4(PDE6C):c.1579C>T (p.Arg527Ter) variant in the homozygous state.

ClinVar ID: 487692

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 36901867

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 2 (16 y, male - brother of Case 1, symptom onset/pain+movement limitation 8 y, diagnosis 16y)

DiseaseAssertion: Scheie syndrome

FamilyInfo: Male patient born to consanguineous parents

CasePresentingHPOs: 0034337

CaseHPOFreeText: claw hands with flexion contractures; electroneurology showed bilateral signs of mild median nerve suffering.

CaseNotHPOs: HP:0000280; HP:0001510; HP:0000943

CaseNotHPOFreeText: no coarse face, growth failure, other joint involvement, evidence of dysostosis multiplex of other bones. Normal intelligence, ophthalmologic, hearing and echocardiography, brain MRI

CaseEnzymeAssay: 0.64 (umol/g/h)

CaseUrineGAGs:

CaseERT: Yes, after diagnosis at 16y CaseBMT:

Variant1:c.1189+4A>T

Variant1ClinVarID:

Variant1CAID: CA2586965965

Variant2: 1189+4A>T

Variant2ClinVarID:

Variant2CAID: CA2586965965

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: Infant B

DiseaseAssertion: MPSI

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: Newborn screening, dried blood spot, modification of method published by Chamoles et al, IDUA activity <9.03 umol/L blood*20 on initial and repeat testing.

CaseUrineGAGs: Urinary GAG obtained as part of confirmatory testing but results are not presented.

CaseERT:

CaseBMT:

Variant1: c.344 G>T (D119Y), paternal origin

Variant1ClinVarID:

Variant1CAID:

Variant2: c.99 T>G (H33Q), maternal origin

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype: c.344 G>T (paternal) / c.99 T>G (maternal)

PreviouslyPublished No

Case#: Infant A

DiseaseAssertion: MPSI

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: Newborn screening, dried blood spot, modification of method published by Chamoles et al, IDUA activity <9.03 umol/L blood*20 on initial and repeat testing.

CaseUrineGAGs: Urinary GAG obtained as part of confirmatory testing but results are not presented.

CaseERT: Don't know

CaseBMT: Don't know

Variant1: 303G > A (R105Q), paternal origin

Variant1ClinVarID: 2020010

Variant1CAID: CA2801866

Variant2: c.484 G>A (R162K), maternal origin

Variant2ClinVarID: 550594

Variant2CAID: CA355961605

AdditionalVariants:

ParentalGenotype: c.303 G>A (paternal) / c.484 G>A (maternal)

PreviouslyPublishedNo

Case#:1 (it is unclear whether the fibroblasts carrying these variants were derived from a single or multiple patients).

DiseaseAssertion: MPS-I

FamilyInfo: not provided

CasePresentingHPO: not provided

CaseHPOFreeText: not provided

CaseNotHPO: not provided

**CaseNotHPOFreeText: not provided

CaseEnzymeAssay:fibroblast iduronidase activity reported but not clear if results are for a single or multiple patients

CaseUrineGAGs: not provided

CaseERT:" Don't know

CaseBMT:Dont' know

Variant1: p.W402X

Variant1ClinVarID: 11908

Variant2: p.W402X

Variant2ClinVarID: 11908

AdditionalVariants: none noted

ParentalGenotypes: not provided

PreviouslyPublished: not specified

PMID: 20586924

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2N

MONDO: 0015631

InheritancePattern: Autosomal Recessive

Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.

Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.

PMID: 31423628

Gene: VWF

HGNC: 12726

PMID: 17000885

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral (PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 2557900

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 23179108

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2B

MONDO: 0015629

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 1409710

Gene: VWF

HGNC: 12726

Disease: von Willebrand disease type 2M

MONDO: 0015630

InheritancePattern: Autosomal Dominant

Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).

Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants

PMID: 42460955

Gene: MYBPC3

HGNC ID: 7551

PMID: 24134628

Gene: MYH7

HGNC: 7577

PMID: 25189259

Gene MYH7

HGNC: 7577

https://www.ias.ac.in/article/fulltext/jgen/093/02/0557-0560

PMID: 24298987

Gene: MYH7

HGNC: 7577

PMID: 23676496

Gene: MYH7

HGNC: 7577

PMID: 27082122

Gene: MYH7

HGNC ID: 7577

Gene: PRKAG2

HGNC ID: 9386

PMID: 23816408

Gene: MYH7

HGNC: 7577

A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias

PMID: 28491642

Gene:ACTC1

HGNC ID:143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID:28491642

Gene:ACTC1

HGNC ID:143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

CasePresentingHPOs: HP:0004756

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 21832052

Gene: MYBPC3

HGNC: 7551

PMID: 24085031

Gene: MYH7

HGNC: 7577

"Defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure"