Submission Details

The IMPG2 gene was first reported in relation to ocular disease in 2010, in affected members of two families who were diagnosed with retinitis pigmentosa with autosomal recessive inheritance (PMID: 20673862). The known spectrum of recessive disease continued to expand with reports of individuals affected with retinitis pigmentosa with relatively early macular involvement (PMID: 24876279) or rod-cone dystrophy (PMID: 31264916). IMPG2 variants were subsequently identified as the basis for autosomal dominant inheritance of vitelliform macular dystrophy (PMID: 25085631), raising the question of whether this disease entity is distinct from retinitis pigmentosa or whether they can occur within the same families. Cases diagnosed with retinitis pigmentosa 56 generally exhibit features such as night blindness, progressive visual loss, macular retinal pigment epithelium (RPE) mottling / atrophy, decreased ERG amplitudes (affecting rods more severely than cones), color vision defect, peripheral visual field loss, central scotoma, retinal blood vessel attenuation, and/or optic disc pallor. These features are largely distinct from the vitelliform macular dystrophy phenotypes, which include foveal vitelliform lesions, dome-shaped foveal detachment with material above the RPE, normal to mildly decreased visual acuity, normal or decreased amplitude ERG responses, and central RPE atrophy. The two disease entities strongly correlate with mode of inheritance, so that biallelic loss-of-function consistently associates with retinitis pigmentosa, while monoallelic loss-of-function consistently associates with vitelliform macular dystrophy. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (monoallelic vs. biallelic IMPG2 loss of function) and mode of inheritance (autosomal dominant vs. autosomal recessive) appear to be distinct between patients with vitelliform macular dystrophy 5 (MIM# 616152) or retinitis pigmentosa 56 (MIM# 613581). Therefore, cases caused by inherited IMPG2 variants have been split into two separate disease entities. The present curation has focused on autosomal recessive cases and is referred to as IMPG2-related recessive retinopathy.

Ten suspected disease-causing variants were scored as part of this curation (five nonsense, one frameshift, one canonical splice site disruption, one in-frame exon deletion, and two missense). These variants have been collectively reported in eight probands in four publications (PMID: 24876279, PMID: 20673862, PMID: 31264916, PMID: 34990796). All eight of the probands scored in this curation harbored two variant alleles within the IMPG2. The mechanism of pathogenicity appears to be biallelic loss of IMPG2 function conferred by null and/or hypomorphic variants. Three families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 24876279). Additional genetic evidence was available but was not necessary to include in this curation, as the maximum for this category of evidence had already been reached.

This gene-disease association is also supported by biochemical evidence that IMPG2 encodes a component of the interphotoreceptor matrix (PMID: 10542133), 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 (PMID: 10601738) and harbors variants associated with vitelliform macular dystrophy 4 and retinitis pigmentosa 91 (PMID: 23993198), PMID: 32817297). Gene expression profiling across human tissues shows that IMPG2 mRNA levels are at their highest in retinal tissues (PMID: 30239781). Zebrafish with morpholino-based Impg2 silencing exhibit decreased cone and rod photoreceptor outer segment length (PMID: 32817297). Mouse models with homozygous CRISPR/Cas9-based Impg2 disruption exhibit a phenotype with features of human retinitis pigmentosa and vitelliform macular dystrophy, including development of subretinal hyper-reflective vitelliform lesions, mislocalization of Impg1, reduction in the amplitudes of rod and cone ERG responses (PMID: 32265257), disorganization of cone-specific markers, pigmentary retinopathy, and enhanced apoptosis / decreased thickness of the outer nuclear layer (PMID: 32242237). Finally, retinal organoids derived from a compound heterozygous patient exhibit defective development of both the inner photoreceptor matrix and outer segment, and can be rescued by correction of both Impg2 alleles (PMID: 36206764).

In summary, IMPG2 is definitively associated with IMPG2-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 August 3rd, 2023 (SOP Version 9).