Case#: Weisschuh_2020_Patient_MDS_342, male, age 73 years at diagnosis, age 75 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with macular dystrophy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant in the heterozygous state.

ClinVar: 493439

gnomAD: The NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006533 (2/30616) in the South Asian population, with no homozygotes https://gnomad.broadinstitute.org/variant/6-76744428-C-T

VariantEvidence: NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) is a nonsense variant in exon 3 of 17, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 84% of the protein product.

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

PMID: 32531858

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.

Case#: Weisschuh_2020_Patient_ARRP_339, male, age 32 years at diagnosis, age 34 years at report, national origin reported as German

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient has been diagnosed with autosomal recessive retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.

CaseMethod1: next generation sequencing-based RET.8 panel

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.

Variant: The patient harbors the NM_001563.4(IMPG1):c.1291+1G>T variant in the homozygous state.

ClinVar: 547007

gnomAD: The NM_001563.4(IMPG1):c.1291+1G>T variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.1291+1G>T is a canonical splice site variant in intron 12 of the 17-exon locus, and does not have evidence of impact on the protein product.

CaseAddInfo: Segregation confirmation in family members is not available.

CasePMIDs: N/A

Case#: Manes_2013_Family_NAL69_Proband_II:4, male, age 43 years at time of report, national origin reported as French

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.58 and 1.68 in each eye), HP:0008275 (Abnormal light-adapted electroretinogram, slightly decreased)

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

CaseNotHPOs: HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)

CaseNotHPOFreeText: N/A

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

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

CaseMethod2: N/A

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

Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) and NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variants in the compound heterozygous state.

ClinVar: 162136, 162135

gnomAD: The NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00007924 (9/113576) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76744345-A-G The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant was found in gnomAD v2.1.1 at a frequency of 0.00004007 (1/24958) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660584-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, another study has reported an apparently unrelated affected patient harboring this variant in the heterozygous state (PMID: 30688845). The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant is a nonsense variant in exon 13 of 17 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product.

CaseAddInfo: The proband has a similarly affected older sister who shares the same genotype. One carrier child is unaffected while the other has a slight defect in one eye within the line separating the inner and outer segments, consistent with incomplete penetrance in the heterozygous state. Consanguinity is not reported in this family.

CasePMIDs: N/A

PMID: 32817297

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.

Selection B- Gene function is consistent with phenotype.

GOterm: GO:0033165 (interphotoreceptor matrix)

FunctionalEvidence: IMPG1 protein can be purified as a component of an insoluble extracellular layer that is located between apical side of the RPE and the external limiting membrane of the neural retina, known as the interphotoreceptor matrix (Figure 1). This layer is known to support the function and maintenance of photoreceptor cells (PMID: 7344830).

FunctionalHPO: HP:0030612 (Abnormal retinal morphology on macular OCT, specifically photoreceptor outer segment elongation), HP:0007677 (Vitelliform-like macular lesions)

PhenotypeEvidence: The article provides an example of the function of IMPG1 (here referred to as IPM150) as a component of the interphotoreceptor matrix, an insoluble extracellular layer that is located between apical side of the RPE and the external limiting membrane of the neural retina, and which supports the adhesion, function, and maintenance of photoreceptor cells.

Case#: Brandl_2017_Family_11-151_Proband_#2, male, age 10 years at time of report, national origin reported as Turkish

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.2 logMAR), HP:0000493 (Abnormal foveal morphology, specifically bilateral central foveal detachment of neurosensory retina), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0030612 (Abnormal retinal morphology on macular OCT)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment. Photoreceptor outer segments were elongated.

CaseNotHPOs: HP:0000512 (Abnormal electroretinogram)

CaseNotHPOFreeText: RPE and Bruch's membrane appeared normal.

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.

CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

Variant: The proband harbors the NM_001563.4(IMPG1):c.807+5G>A variant in the homozygous state.

ClinVar: 1240016

gnomAD: The NM_001563.4(IMPG1):c.807+5G>A variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_001563.4(IMPG1):c.807+5G>A is an intron 7 variant that has mini-gene assay evidence from this article (Figure 1) confirming a partial deleterious impact on the splicing of the transcript. The variant triggers skipping of exon 7 in approximately half of the transcripts. This partial defect appears to lead to in-frame loss of 141 bp (47 amino acids) corresponding to ~6% of the protein product.

CaseAddInfo: The parents of the proband are consanguineous and are clinically asymptomatic at ages 35 and 40 years, respectively.

CasePMIDs: N/A

Case#: Brandl_2017_Family_13-501_Proband_#1, male, age 13 years at time of report, national origin reported as German

CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.1 to 0.2 logMAR), HP:0007703 (Abnormality of retinal pigmentation, particularly in the center), HP:0000493 (Abnormal foveal morphology, specifically foveal detachment)

CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.

CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

CaseMethod2: N/A

CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.

Variant: The proband harbors the NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant in the heterozygous state.

ClinVar: 865770

gnomAD: The NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00006598 (2/30310) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728530-G-A?dataset=gnomad_r2_1

VariantEvidence: NM_001563.4(IMPG1):c.713T>C (p.Leu238Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, it has been reported by an independent group of researchers in multiple families with vitelliform macular dystrophy (PMID: 23993198).

CaseAddInfo: The proband is the only family member affected, with clinical and genetic testing data on the parents unavailable.

CasePMIDs: N/A

FamilyLabel: van_Lith-Verhoeven_2004_Family

Family#PresentingHPOs: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

FamilyPresentingHPOFreeText: The affected family members have been diagnosed with benign concentric annular macular dystrophy (BCAMD), segregating with an autosomal dominant mode of inheritance. Visual acuity was initially normal but progressed to phenotype similar to retinitis pigmentosa, including peripheral retinal involvement and photoreceptor cell dysfunction (shown by ERG).

FamilyNotHPOs: HP:0000613 (Photophobia), HP:0000551 (severe Color vision defect)

FamilyNotHPOFreeText: N/A

CountryOrigin: The family is reportedly Dutch.

Ethnicity: Not specifically described

Race: N/A

Family#PreviousTesting: Linkage analysis was performed using a combination of a whole genome scan and microsatellite markers within candidate retinal loci.

Family#Method1: Genome-wide and candidate-focused linkage analyses

Family#Method2: Sanger sequencing of the candidate genes ELOVL4, GABR1, GABR2 and IMPG1

Family#GenotypingMethod: Linkage analysis was performed using a genome-wide scan as well as microsatellite markers from candidate loci. Sanger sequencing then analyzed the candidate retina genes from the linkage region; ELOVL4, GABR1, GABR2 and IMPG1

Affected: 11 genotyped

Unaffected: 5 genotyped

Segregations: 10 segregations are shown by the pedigree in Figure 1.

PublishedLOD: 3.8

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: van_Lith-Verhoeven_2004_Family_Proband_II-4

Variant: The affected family members harbor the NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) variant in the heterozygous state.

ClinVar: 1008228

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

VariantEvidence: NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) is a missense variant that does not have evidence confirming an impact on the gene product.

FamilyAddInfo: The family's national origin has been reported as Dutch.

FamilyPMIDs: N/A

ExperimentName: CRISPR/Cas9-based disruption of mouse Impg1

NonHumanModel: Mus musculus

GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 10bp from exon 2 of Impg1, and analyzed in the homozygous state. Absence of Impg1 signal was confirmed by immunofluorescent staining. Mice were studied at ages 5 months and 8 months.

ModelPhenotype: HP:0030612 (Abnormal retinal morphology, specifically mislocalization of chondroitin sulfate in the IPM, with none in the outer segment and more in the inner segment)

HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)

ModelEvidence: This is the first mouse model of Impg1 disruption, with confirmed absence of Impg1 in the homozygous animals. The only observed abnormality is mislocalization of chondroitin sulfate in the IPM, with none in the outer segment and more in the inner segment (Figure 7). A mild disruption was observed in the localization of PNA, a cone-specific marker, to the outer segment (Fig. 2F). Impg2 appears to be normally localized (Figure 2C). ERG responses were normal (data not shown). Please note that an independent study generating a different model of homozygous Impg1 disruption reported different findings (PMID: 36140676).

ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg1 ortholog.

ExperimentName: Blocking IMPG1 in retinal organoids disrupts early development of IPM, photoreceptors and inner/outer segments, and connecting cilia.

NonPatientCell: UBERON:0000966 (retina, specifically IPSC-derived retinal organoids) or CL:0009004 (retinal cell)

GeneFunction: GO:0033165 (interphotoreceptor matrix)

GeneAlteration: Alteration was not performed at the genetic level, but rather a blocking antibody to IMPG1 protein was added to the culture media of the developing retinal organoid at days 90 and 150 of the differentiation process. After incubation, the effects were assessed by IHC and qRT-PCR detecting key markers of differentiation (Figure 6, Figures S12-S15).

FunctionalEvidence: Expression of RCVRN (a marker of photoreceptor and bipolar cells) and proportion of recoverin-positive cells were reduced (Figs. 6B, S12B, S14B, S14C, S15B). Expression of ARL13B (marker of photoreceptor connecting cilia) was reduced (Figs. 6B, S15B). Expression of RBP3 (marker of IPM formation) was changed only at the later time point (Figs. 6B, S12B, S15B). Expression of OPN1LW/OPN1MW (cone marker) was down-regulated (Fig. S14B). Expression of RHO (rod cell marker) and proportion of rhodopsin-positive cells were reduced, and the typical pattern of staining was replaced with a punctate pattern at the surface of the organoids (Fig. 6B, 6C). Staining for WGA (rod inner/outer segment marker) was reduced, indicating disrupted development of these structures (Fig. 6B, 6C). The authors conclude that IMPG1 is important for development of photoreceptors, inner and outer segments, connecting cilia, and IPM.

FAVariants: No variant in IMPG1 was used, but rather an inhibitory antibody.