Expanding the Genetic Spectrum in IMPG1 and IMPG2 Retinopathy

<b><i>Background:</i></b> Pathogenic variants in interphotoreceptor matrix proteoglycan 1 (<i>IMPG1</i>) have been associated with autosomal dominant and recessive retinitis pigmentosa (RP) and autosomal dominant adult vitelliform macular dystrophy (AVMD). Monoallelic pathogenic variants in <i>IMPG2</i> have been linked to maculopathy and biallelic variants to RP with early onset macular atrophy. Herein we characterise the phenotypic and genotypic features of patients with IMPG1/IMPG2 retinopathy and report novel variants. <b><i>Methods</i></b>: Patients with <i>IMPG1</i> and <i>IMPG2</i> variants and compatible phenotypes were retrospectively identified. Clinical data were obtained from reviewing the medical records. Phenotypic data included visual acuity, imaging included ultra-widefield pseudo-colour, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using next generation sequencing (NGS). Variant pathogenicity was investigated using in silico analysis (SIFT, PolyPhen-2, mutation taster, SpliceAI). The evolutionary conservation of novel missense variants was also investigated. <i><b>Results</b></i>: A total of 13 unrelated patients were identified: 2 (1 male; 1 female) with <i>IMPG1</i> retinopathy and 11 (7 male; 4 female) with <i>IMPG2</i> retinopathy. Both <i>IMPG1</i> retinopathy patients were monoallelic: one patient had adult vitelliform macular dystrophy (AVMD) with drusenoid changes while the other had pattern dystrophy (PD), and they presented to clinic at age 81 and 72 years, respectively. There were 5 monoallelic <i>IMPG2</i> retinopathy patients with a maculopathy phenotype, of whom 1 had PD and 4 had AVMD. The mean age of symptom onset of this group was 54.2 ± 11.8 years, mean age at presentation was 54.8 ± 11.5 years, and mean BCVAs were 0.15 ± 0.12 logMAR OD and -0.01 ± 0.12 logMAR OS. Six biallelic <i>IMPG2</i> patients had RP with maculopathy, where the mean age of onset symptom onset was 18.4 years, mean age at examination was 68.7 years, and mean BCVAs were 1.90 logMAR OD and 1.82 logMAR OS. Variants in <i>IMPG1</i> included one missense and one exon deletion. A total of 11 different <i>IMPG2</i> variants were identified (4 missense, 7 truncating). A splicing defect was predicted for the c.871C>A p.(Arg291Ser) missense <i>IMPG2</i> variant. One <i>IMPG1</i> and five <i>IMPG2</i> variants were novel. <b><i>Conclusions</i></b>: This study describes the phenotypic spectrum of <i>IMPG1</i>/<i>IMPG2</i> retinopathy and six novel variants are reported. The phenotypes of PD and AVMD in monoallelic <i>IMPG2</i> patients may result from haploinsufficiency, supported by the presence of truncating variants in both monoallelic and biallelic cases. The identification of novel variants expands the known genetic landscape of <i>IMPG1</i> and <i>IMPG2</i> retinopathies. These findings contribute to diagnostic accuracy, informed patient counselling regarding inheritance pattern, and may help guide recruitment for future therapeutic interventions.