IMPG1

Inheritance Pattern: AD

Disease ID:MONDO:0014508

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0014508

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011979

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:1040037

Submitter: ClinGen

The *IMPG1* gene was first reported in relation to ocular disease in 2004, in affected members of a family with an autosomal dominant pattern of inheritance (PMID: 14691150). The known spectrum of disease expanded to include cases with autosomal recessive inheritance with the 2013 identification of *IMPG1* variants in association with vitelliform macular dystrophy (PMID: 23993198). *IMPG1* variants have also been identified as the basis for cases of retinitis pigmentosa with both autosomal dominant (PMID: 32817297) and autosomal recessive (PMID: 32817297) modes of inheritance, indicating the potential for a broad range of phenotypic presentations. Autosomal recessive cases diagnosed with retinitis pigmentosa 91 generally exhibit features such as night blindness, bone spicule pigmentation of the retina, drusen, a ring of hyper-autofluorescence, retinal thinning / fundus atrophy, retinal blood vessel attenuation, and/or optic disc pallor. Reported cases diagnosed as vitelliform macular dystrophy 4 generally exhibit features such as vitelliform-like macular lesions, foveal detachment, small yellow foveal spots, and/or choroidal neovascularization. Some of the retinitis pigmentosa and vitelliform macular dystrophy cases are reported with reduced visual acuity and reduced electroretinogram (particularly dark-adapted) responses. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic *IMPG1* loss of function) was found to be consistent among patients with recessive inheritance of vitelliform macular dystrophy (MIM# 616151) or retinitis pigmentosa (MIM# 153870), The phenotypic variability between them appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *IMPG1* variants have been lumped into a single disease entity, referred to as IMPG1-related recessive retinopathy. On the other hand, carriers from families with autosomal recessive disease have only been subclinically affected, prompting the group to recommend splitting the autosomal dominant cases into a separate curation for IMPG1-related dominant retinopathy. Eight suspected disease-causing variants were scored as part of this curation (one nonsense, four affecting splicing, and three missense), which have been collectively reported in seven probands in four publications (PMID: 23993198, PMID: 28644393, PMID: 32817297, PMID: 32531858). All of the probands scored in this curation harbored biallelic *IMPG1* variants. The mechanism of pathogenicity appears to be biallelic loss of *IMPG1* function conferred by null and/or hypomorphic variants. Interestingly, biallelic variants appear to be associated with complete penetrance, while monoallelic variants are generally incompletely penetrant. Large families with a recessive mode of inheritance were not found in the literature, and segregation evidence did not contribute to the scoring of this curation. This gene-disease association is also supported by biochemical evidence that *IMPG1* encodes a component of the interphotoreceptor matrix (PMID: 10601738), an insoluble extracellular layer located between the retinal pigment epithelium and the neural retina that is known to support the function and maintenance of photoreceptor cells (PMID: 7344830). The *IMPG2* gene similarly encodes a component of this structure and harbors variants associated with vitelliform macular dystrophy 5 and retinitis pigmentosa 56 (PMID: 10542133, PMID: 10601738). Gene expression profiling across human tissues shows that *IMPG1* mRNA levels are at their highest in retinal tissues (PMID: 30239781). Within the eye, *IMPG1* expression is detected in cone and rod photoreceptor cells, specifically in the outer nuclear layer (PMID: 10601738). IMPG1-blocking antibody treatment has been shown to disrupt the differentiation of retinal organoids, indicating a role for IMPG1 in the development of photoreceptors, inner and outer segments, connecting cilia, and the interphotoreceptor matrix (PMID: 29777959). Mouse models of homozygous *Impg1* loss-of-function have shown minimal abnormalities limited to the interphotoreceptor matrix during the first 8 months of life (PMID: 32265257), but exhibit late-developing phenotypes between 9 and 14 months of age, such as hyperpigmented subretinal deposits, nummular pigmentation of the fundus, attenuated ERG response, reduced retinal thickness in the outer layer, photoreceptor cell loss, and disorganization of the interphotoreceptor matrix (PMID: 36140676). In summary, *IMPG1* is definitively associated with IMPG1-related recessive retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on September 7th, 2023 (SOP Version 9).

Inheritance Pattern: SD

Disease ID:MONDO:0019118

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Franklin by Genoox

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: Franklin by Genoox

Inheritance Pattern: AD

Disease ID:MONDO:1040036

Submitter: ClinGen

The *IMPG1* gene was first reported in relation to ocular disease in 2004, in affected members of a family who were initially diagnosed with benign concentric macular dystrophy (PMID: 14691150) and revised during subsequent follow-up to autosomal dominant retinitis pigmentosa (PMID: 32817297). The known spectrum of disease continued to expand with the 2013 identification of *IMPG1* variants in cases of vitelliform macular dystrophy, with either autosomal dominant or autosomal recessive modes of inheritance (PMID: 23993198). *IMPG1* variants have since been identified as the basis for autosomal dominant inheritance of cone dystrophy or maculopathy as well (PMID: 32817297), indicating the potential for a broad range of phenotypic presentations. Autosomal dominant cases diagnosed with retinitis pigmentosa 91 generally exhibit features such as night blindness, bone spicule pigmentation of the retina, drusen, a ring of hyper-autofluorescence, retinal thinning / fundus atrophy, peripheral retinal degeneration, retinal blood vessel attenuation, and/or optic disc pallor. Reported cases diagnosed as vitelliform macular dystrophy 4 generally exhibit features such as vitelliform-like macular lesions, foveal detachment, small yellow foveal spots, and/or choroidal neovascularization. Some of the retinitis pigmentosa and vitelliform macular dystrophy cases are reported with reduced visual acuity and reduced electroretinogram (particularly dark-adapted) responses. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (monoallelic *IMPG1* loss of function) was found to be consistent among patients with dominant inheritance of vitelliform macular dystrophy (MIM# 616151) or retinitis pigmentosa (MIM# 153870), The phenotypic variability between them appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited monoallelic *IMPG1* variants have been lumped into a single disease entity, referred to as IMPG1-related dominant retinopathy. On the other hand, carriers from families with autosomal recessive disease have only been subclinically affected, prompting the group to recommend splitting the autosomal recessive cases into a separate curation for IMPG1-related recessive retinopathy. Six suspected disease-causing variants were scored as part of this curation (two nonsense, one affecting splicing, and three missense), which have been collectively reported in nine probands in five publications (PMID: 14691150, PMID: 23993198, PMID: 28644393, PMID: 32817297, PMID: 32531858). All of the probands scored in this curation harbored only one variant allele within the IMPG1 locus. The mechanism of pathogenicity appears to be monoallelic loss of *IMPG1* function conferred by null and/or hypomorphic variants. While monoallelic variants are generally incompletely penetrant, three families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 14691150, PMID: 23993198, PMID: 32817297). This gene-disease association is also supported by biochemical evidence that *IMPG1* encodes a component of the interphotoreceptor matrix (PMID: 10601738), an insoluble extracellular layer located between the retinal pigment epithelium and the neural retina that is known to support the function and maintenance of photoreceptor cells (PMID: 7344830). The *IMPG2* gene similarly encodes a component of this structure and harbors variants associated with vitelliform macular dystrophy 5 and retinitis pigmentosa 56 (PMID: 10542133, PMID: 10601738). Gene expression profiling across human tissues shows that *IMPG1* mRNA levels are at their highest in retinal tissues (PMID: 30239781). Within the eye, *IMPG1* expression is detected in cone and rod photoreceptor cells, specifically in the outer nuclear layer (PMID: 10601738). IMPG1-blocking antibody treatment has been shown to disrupt the differentiation of retinal organoids, indicating a role for IMPG1 in the development of photoreceptors, inner and outer segments, connecting cilia, and the interphotoreceptor matrix (PMID: 29777959). Mouse models of homozygous *Impg1* loss-of-function have shown minimal abnormalities limited to the interphotoreceptor matrix during the first 8 months of life (PMID: 32265257), but exhibit late-developing phenotypes between 9 and 14 months of age, such as hyperpigmented subretinal deposits, nummular pigmentation of the fundus, attenuated ERG response, reduced retinal thickness in the outer layer, photoreceptor cell loss, and disorganization of the interphotoreceptor matrix (PMID: 36140676). In summary, *IMPG1* is definitively associated with IMPG1-related dominant retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on September 7th, 2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0014508

Submitter: Labcorp Genetics (formerly Invitae)