ExperimentName: Murine model of PDE6A loss-of-function (Pde6Anmf363/nmf363)

NonHumanModel: Mus musculus

GeneAlteration: Mice were found to develop retinal degeneration due to a homozygous missense variant (2159G>A) at codon 670 substituting glycine for aspartic acid.

ModelPhenotype: HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0030478 (Abnormal amplitude of dark-adapted bright flash electroretinogram)

HumanPhenotype: HP:0011463 (Childhood onset), 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), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: This mutation caused photoreceptor outer nuclear layer outer segment thinning (Figures 2C, 2D, 7), decreased dark-adapted bright flash ERG amplitude (Figure 2E), and decreased cGMP/PDE activity (Figure 3C).

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a mutagenesis-induced missense variant disrupting Pde6a leading to partial loss-of-function.

PMID: 18849587

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.

PMID: 227876

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: PDE6A forms a complex with PDE6B and PDE6G

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

InteractionType: physical

InteractionMethod: size exclusion chromatography

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

Case#: Corton_2010_Family_RP-72_patient_IV:2, male, age 35 years at time of study, age 6 at onset, Spanish family origin from Galicia

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0030526 (Severe constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Haplotype analysis was initially performed in the patient and his affected family members.

CaseMethod1: Haplotype analysis

CaseMethod2: Sanger sequencing of PDE6A, PDE6B, and RHO

CaseGenotypingMethod: Haplotype analysis was initially performed in the patient and his affected family members, showing shared regions of homozygosity in the PDE6A, PDE6B, and RHO genes. Sanger sequencing was then performed on PCR products of exons and flanking regions from these three loci.

Variant: The proband harbors the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.

ClinVar: 29874

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

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

CaseAddInfo: The proband is from a family with multiple consanguineous unions and three affected paternal aunts.

CasePMIDs: N/A

FamilyLabel: Corton_2010_Family_RP-72

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

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Spain / Galicia

Ethnicity: Spanish

Race: Not specifically described

Family#PreviousTesting: N/A

Family#Method1: Haplotype analysis

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

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

Affected: 4

Unaffected: 5 fully genotyped

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

PublishedLOD: N/A

eLOD: 2.43

AddSegregationInfo: N/A

ProbandLabel: Corton_2010_Family_RP-72_patient_IV:2

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

ClinVar: 29874

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

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

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

FamilyPMIDs: N/A

PMID: 21039428

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

Case#: Jespersgaard_2019_Patient_163, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant in the homozygous state.

ClinVar: 636056

gnomAD: The NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant is not found in gnomAD v2.1.1.

VariantEvidence: NM_000440.3(PDE6A):c.612del (p.Lys205fs) is a frameshift variant in exon 2 that is predicted to result in nonsense-mediated decay or at least to truncate the C-terminal ~76% of the protein product.

CaseAddInfo: N/A

CasePMIDs: N/A

Case#: Jespersgaard_2019_Patient_165, gender and age not specified, origin likely to be Danish based on cohort

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

Variant: The proband harbors the NM_000440.3(PDE6A):c.1620+1G>A variant in the homozygous state.

ClinVar: 636054

gnomAD: The NM_000440.3(PDE6A):c.1620+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149275918-C-T

VariantEvidence: The NM_000440.3(PDE6A):c.1620+1G>A variant disrupts a canonical splice site in intron 12, but does not have experimental confirmation of exon skipping or frameshift.

CaseAddInfo: N/A

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

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

ClinVar: 636057

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

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

ClinVar: 636052, 636051

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 30718709

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

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

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

CaseMethod1: NGS panel

CaseMethod2: N/A

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

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

ClinVar: 636053

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

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

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 18775863

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

ExperimentName: Canine model of PDE6A loss-of-function

NonHumanModel: Canis lupus familiaris

GeneAlteration: Cardigan Welsh Corgi animals were found to develop retinal degeneration due to a homozygous 1-bp deletion variant at codon 616 that results in a frameshift and a premature stop codon (genotype previously reported in PMID: 10393029).

ModelPhenotype: HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0000505 (Visual impairment), HP:0007843 (Attenuation of retinal blood vessels), HP:0030610 (Photoreceptor outer segment loss on macular OCT)

HumanPhenotype: HP:0011463 (Childhood onset), 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), HP:0007984 (Electronegative electroretinogram)

ModelEvidence: This mutation caused an Electronegative electroretinogram (HP:0007984) and Abnormal light-adapted electroretinogram (HP:0008275), (Figures 2, 3, and 4). Retinal degeneration (HP:0000546) was observed with outer nuclear photoreceptor layer thinning (HP:0030610, Figure 5). Photoreceptor outer segment loss is visible on macular OCT (Figure 6, Figure 7), particularly loss of rod photoreceptor cells.

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a naturally occurring frameshift variant disrupting Pde6a leading to full loss-of-function.

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: 20940301

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.

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.

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: 26321862

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

Case#: Huang_1995_Family_#3397_Patient_AR76, male, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), 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), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and his affected sibling were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) and NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) variants in the compound heterozygous state.

ClinVar: 13111, 13112

gnomAD: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) was not found in gnomAD v2.1.1, while NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) was found at a frequency of 0.000008792 (1/113736) in the European non-Finnish population. https://gnomad.broadinstitute.org/variant/5-149274791-C-T

VariantEvidence: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) is a missense variant in exon 7 of 22 total, and does not have evidence of a functional effect on the protein product. NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) is a nonsense variant in exon 13 of 22 total, and is predicted to trigger NMD or to at least disrupt the C-terminal 35% of the protein product.

CaseAddInfo: The proband is from a family with an affected sibling and unaffected parents.

CasePMIDs: N/A

Case#: Huang_1995_Family_#3526_Patient_AR23, female, age and ethnic origin note mentioned

CasePresentingHPOs: HP:0011463 (Childhood onset), 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), HP:0007984 (Electronegative electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.

CaseMethod1: SSCP

CaseMethod2: Sanger sequencing of PDE6A

CaseGenotypingMethod: The patient and her affected family members were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.

Variant: The proband harbors the NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) variant in the homozygous state.

ClinVar: 13110

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

VariantEvidence: NM_000440.3(PDE6A):c.1749C>G (p.Tyr583Ter) is a nonsense variant in exon 14 of 22 total, and is predicted to trigger NMD or to at least truncate ~32% of the protein product.

CaseAddInfo: The proband is from a family with two affected siblings, two unaffected siblings, and unaffected parents.

CasePMIDs: N/A

PMID: 7493036

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.

PMID: 28676737

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: Rescue of Pde6a-mutant Cardigan Welsh Corgi dogs with canine Pde6a

RescueModel: Canis lupus familiaris

GeneAlteration: The model harbors a homozygous 1-bp deletion variant at codon 616 that results in a frameshift and a premature stop codon (previously reported in PMID: 10393029 and PMID: 18775863).

RescueVariant: Rescue was performed with wild-type canine Pde6a delivered by AAV8 and expressed under the CMV-chicken beta-actin promoter, in comparison to a GFP control.

RescuePhenotype: HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0000505 (Visual impairment), HP:0007843 (Attenuation of retinal blood vessels), HP:0030610 (Photoreceptor outer segment loss on macular OCT)

RescueMethod: Rescue was performed by subretinal injection of AAV8 particles delivering wild-type canine Pde6a or GFP cDNA (Figures 4, 5, and 6).

RescueEvidence: Rod ERG response shows improvement from undetectable to detectable following AAV-Pde6a injection (Fig. 1). Visual impairment also improved according to visual navigation ability (Fig. 2). Attenuation of retinal blood vessels was prevented as well (Fig. 3). Photoreceptor outer nuclear layer thickness was preserved (Fig. 4). Finally, treatment promoted rod photoreceptor survival (Fig. 5).

ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a naturally occurring frameshift variant disrupting Pde6a leading to full loss-of-function.

Case#: Riazuddin_2006_61074_patient_10, male, age 25 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61074 harbor the NM_000440.3(PDE6A):c.1408-2A>G variant in the homozygous state.

ClinVar: 225119

gnomAD: This variant is present in gnomAD v2.1.1 at a frequency of 0.00003266 (1/30616 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149276341-T-C

VariantEvidence: NM_000440.3(PDE6A):c.1408-2A>G is a variant disrupting a splice acceptor site in intron 10 that is predicted to result in exon 11 skipping, truncating 22 amino acids (~3%) of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

Case#: Riazuddin_2006_61021_patient_12, female, age 33 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61021 harbor the NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) variant in the homozygous state.

CAID: CA2573332091

gnomAD: This variant is absent from gnomAD v2.1.1.

VariantEvidence: NM_000440.3:c.2098dup (p.Tyr700LeufsTer21) is a frameshift variant in exon 17 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~19% of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

PMID: 17110911

Gene: PDE6A

HGNC: 8785

Disease: retinitis pigmentosa 43

MONDO: MONDO:0013437

InheritancePattern: autosomal recessive

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

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

Case#: Riazuddin_2006_Family_61019_patient_20, female, age 18 years at time of study, Pakistani family origin from remote Punjab province

CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

CaseMethod1: Genome-wide linkage analysis

CaseMethod2: Sanger sequencing of the candidate gene PDE6A

CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on all four families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Variant: The affected members of Family 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.

ClinVar: 437984

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A

VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.

CaseAddInfo: The patient is from a family with consanguineous unions.

CasePMIDs: N/A

FamilyLabel: Riazuddin_2006_Three_Families

Family#PresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)

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

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: Pakistan

Ethnicity: Pakistani (reportedly with origin from remote parts of Punjab province)

Race: Not specifically described

Family#PreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.

Family#Method1: Genome-wide linkage analysis

Family#Method2: Sanger sequencing of the candidate gene PDE6A

Family#GenotypingMethod: Genome-wide linkage analysis was initially performed on all four families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.

Affected: 12 genotyped

Unaffected: 7 genotyped

Segregations: 18 segregations are shown by the three pedigrees in Figure 3.

PublishedLOD: 7.4172

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Riazuddin_2006_Family_61019_Proband

Variant: The affected members of Family 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.

ClinVar: 437984

gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A

VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.

FamilyAddInfo: All three families are reportedly consanguineous.

FamilyPMIDs: N/A

PMID: 10393029

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.