PMID: 28644393

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

Case#: Bandah-Rozenfeld_2010_NAP1_proband, female, age 30 years at time of diagnosis, in the 6th decade of life at the time of report, national origin reported as Italian

CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0032122 (Very low visual acuity), HP:0000577 (Exotropia), HP:0000639 (Nystagmus), HP:0007787 (Posterior subcapsular cataract), HP:0000550 (Undetectable electroretinogram)

CaseHPOFreeText: The patient has been diagnosed with advanced retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

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

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant in the homozygous state.

ClinVar: 3549

gnomAD: The NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006152 (1/16256, with 0 homozygotes) in the African / African-American population. https://gnomad.broadinstitute.org/variant/3-100961664-G-A

VariantEvidence: NM_016247.4(IMPG2):c.2890C>T (p.Arg964Ter) is a nonsense variant in exon 14 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 22% of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being second cousins.

CasePMIDs: N/A

PMID: 20673862

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

Case#: Bandah-Rozenfeld_2010_MOL0732_proband, female, age 63 years at time of diagnosis, ethnic origin reported as Israeli Christian Arab

CasePresentingHPOs: HP:0008002 (Abnormality of macular pigmentation), HP:0030613 (Abnormal foveal morphology on macular OCT), HP:0030557 (Best corrected visual acuity 0.4 LogMAR), HP:0000603 (Central scotoma), HP:0031729 (Moderate hypermetropia), HP:0000518 (Cataract)

CaseHPOFreeText: The patient has been diagnosed with mild maculopathy. "Abnormal foveal morphology" refers to elevation of the photoreceptor layer in foveal region by OCT analysis. The "cataract" specifically refers to mild nuclear sclerosis.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0000551 (Color vision defect)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.

CaseMethod1: Homozygosity mapping

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

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant in the homozygous state.

ClinVar: 3550

gnomAD: The NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001318 (17/129010, with 0 homozygotes) in the European (non-Finnish) population. https://gnomad.broadinstitute.org/variant/3-101023121-A-G

VariantEvidence: NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) is a missense variant in exon 3 of 19 that does not have evidence of impact on the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins.

CasePMIDs: A publication by a separate group referred to this case as autosomal recessive vitelliform macular dystrophy, but did not indicate the existence of any additional details about the case (PMID: 25085631).

PMID: 23105016

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

PMID: 36206764

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

ExperimentName: Patient iPSC-derived retinal organoids exhibit severe outer segment defects that can be rescued by CRISPR/Cas9-based editing.

RescuePatientCell: EFO:0004905 (induced pluripotent stem cell, differentiated into a retinal organoid)

GeneAlteration: The patient cells have inherited compound heterozygous variants in IMPG2, encoding either p.Tyr254Cys or a frameshift variant starting at codon 805.

RescuePhenotype: Patient iPSC-derived retinal organoids harboring these two variants exhibited almost complete failure to form an outer segment or an interphotoreceptor matrix during a 200-day period (Figure 2A), relative to control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D).

RescueMethod: CRISPR/Cas9-based editing was used to correct both variants.

RescueEvidence: Control retinal organoids with CRISPR/Cas9-based editing / rescue of both variants (Figure 2D) showed development of both the IPM and the outer segment, relative to the uncorrected retinal organoids (Figure 2A). This rescue argues for a role of IMPG2 in photoreceptor cell outer segment development / maintenance.

RescueVariants: NM_016247.4:c.761A>G (p.Tyr254Cys, CA353867908) and an undefined frameshift variant at codon 805, either NM_016247.4:c.2413del (p.Ala805LeufsTer8) or NM_016247.4:c.2414del (p.Ala805ValfsTer8).

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 7bp from exon 3 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by immunofluorescent staining. Mice were studied at ages 5 months and 8 months.

ModelPhenotype: HP:0030612 (Abnormal retinal morphology, specifically mislocalization / scattering of IMPG1 throughout the outer segment and at the boundary with the RPE), HP:0030643 (Vitelliform-like subretinal lesions), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)

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

ModelEvidence: This is the first mouse model of Impg2 disruption, with confirmed absence of Impg2 in the homozygous animals. Abnormalities included mislocalization of Impg1 and the cone-specific marker Pna (Figure 2), accumulation of anomalous material between the photoreceptor outer segment and RPE (Figure 3), development of subretinal hyper-reflective vitelliform lesions (Figure 4), and reduction in the amplitudes of ERG responses from both rods (Figure 5A) and cones (Figure 5B).

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

PMID: 32265257

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

FamilyLabel: van_Huet_2014_Family_F, family national origin reported as from Pakistan

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina)

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Pakistan

Ethnicity: Not mentioned

Race: Not mentioned

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

Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene

Family#Method2: N/A

Family#GenotypingMethod: 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.

Affected: 3

Unaffected: 3

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_F-II:2

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.

ClinVar: 437938

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

FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.

FamilyPMIDs: N/A

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

FamilyLabel: van_Huet_2014_Family_B, ethnic origin reported as Iraqi Jewish

Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), 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)

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Iraq

Ethnicity: Reported as Iraqi Jewish

Race: Not mentioned

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

Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene

Family#Method2: N/A

Family#GenotypingMethod: 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.

Affected: 3

Unaffected: 0

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.20

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_B-II:1

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.

FamilyPMIDs: N/A

PMID: 24876279

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch

Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), 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)

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

Family#PresentingNotHPOs: N/A

CountryOrigin: Netherlands

Ethnicity: Reported as Dutch

Race: Not mentioned

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

Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene

Family#Method2: N/A

Family#GenotypingMethod: 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.

Affected: 3

Unaffected: 3

Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently not consanguineous. The pedigree is shown in Figure 1.

PublishedLOD: N/A

eLOD: 1.50

AddSegregationInfo: N/A

ProbandLabel: van_Huet_2014_Patient_A-II:1

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.

FamilyAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous.

FamilyPMIDs: N/A

Case#: van_Huet_2014_Patient_F-II:2, female, age 10 years at time of onset, age 32 at the time of report, national origin reported as from Pakistan

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0011504 (Bull's eye maculopathy), HP:0100014 (Epiretinal membrane), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration), 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: HP:0000517 (Abnormal lens morphology, such as cataract)

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.1680T>A (p.Tyr560Ter) variant in the homozygous state.

ClinVar: 437938

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

VariantEvidence: The NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 55% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has an affected brother and an affected mother who have the same genotype, as well as a heterozygous carrier father.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_H-II:6, female, age 17 years at time of onset, age 46 years at the time of report, national origin reported as Dutch

CasePresentingHPOs: Nyctalopia HP:0000662, HP:0011462 (Young adult onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000518 (Cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram), HP:0011510 (Drusen)

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 consisted of autozygosity mapping (PMID: 20673862).

CaseMethod1: Homozygosity mapping

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

CaseGenotypingMethod: Genotyping consisted of autozygosity mapping (PMID: 20673862) followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The affected family members harbor the NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) and NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variants in the compound heterozygous state.

ClinVar: 191181, 3548

gnomAD: These two variants were not found in gnomAD v2.1.1.

VariantEvidence: The NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) variant is a nonsense variant in exon 4 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 86% of the protein product. The NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 27% of the protein product.

CaseAddInfo: The family is reportedly non-consanguineous, and the patient has a similarly affected sister with the same genotype. Segregation of the two variants has been demonstrated within the family.

CasePMIDs: PMID: 20673862

Case#: van_Huet_2014_Patient_B-II:1, female, in childhood at time of onset, age 66 at the time of report, national origin reported as Iraqi Jewish

CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0011003 (High myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0100018 (Nuclear cataract), HP:0030856 (Posterior staphyloma), HP:0007401 (Macular 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), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

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.635C>G (p.Ser212Ter) variant in the homozygous state.

ClinVar: 3546

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

VariantEvidence: The NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant is a nonsense variant in exon 6 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 83% of the protein product.

CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has two affected sisters who share the same genotype, and each parent is a heterozygous carrier.

CasePMIDs: PMID: 20673862

PMID: 25085631

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2

NonHumanModel: Mus musculus

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

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

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

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

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

PMID: 32242237

Gene: IMPG1

HGNC: 6055

Disease: vitelliform macular dystrophy 4

MONDO: 0014508

InheritancePattern: semi-dominant

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

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

ExperimentName: Morpholino-based disruption of Impg2 in medaka fish

NonHumanModel: Oryzias latipes

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

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

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

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

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

PMID: 31264916

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

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

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

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

CaseNotHPOs: HP:0000639 (Nystagmus)

CaseNotHPOFreeText: N/A

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

CaseMethod1: retinal dystrophy gene panel

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

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

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

ClinVar: 978976

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

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

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

CasePMIDs: N/A

PMID: 34990796

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

Case#: Chatterjee_2022_proband_II:4, female, age 16 years at time of report, onset in second decade of life, geographic origin reported as north Indian

CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000613 (Photophobia), HP:0000662 (Nyctalopia), HP:0030564 (Best corrected visual acuity 1.1 LogMAR), HP:0025147 (Beaten bronze macular sheen), HP:0011507 (Macular flecks), HP:0030619 (Reduced OCT-measured foveal thickness), HP:0025010 (Foveal atrophy)

CaseHPOFreeText: The patient and siblings have been diagnosed with Stargardt-like juvenile macular dystrophy.

CaseNotHPOs: HP:0007737 (Bone spicule pigmentation of the retina)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of whole-exome sequencing.

CaseMethod1: whole-exome sequencing

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

CaseGenotypingMethod: Genotyping consisted of whole-exome sequencing followed by Sanger sequencing of the 19 exons of the IMPG2 gene.

Variant: The patient harbors the NM_016247.4:c.1239+1G>T variant in the homozygous state.

CAID: CA353864391

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

VariantEvidence: NM_016247.4:c.1239+1G>T is a canonical splice site variant in intron 11 of the 19-exon locus that has been shown by mini-gene assay to trigger a splicing defect that leads to complete skipping of exon 11. Because this would lead to a shift of frame, the variant is predicted to lead to a premature stop after codon 385 and either NMD or truncation of 69% of the C-terminus of the protein product.

CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant. The patient has two affected siblings who share the same genotype.

CasePMIDs: N/A

Patient G000986 has retinitis pigmentosa and is a compound heterozygote harboring two IMPG2 variants ().

PMID: 28041643

Gene: IMPG2

HGNC: 18362

Disease: retinitis pigmentosa 56

MONDO: 0013314

InheritancePattern: semi-dominant

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

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

PMID: 28771251

PMID: 35608844