IMPG2-associated unilateral adult onset vitelliform macular dystrophy

Georgiou, Michalis; Chauhan, Muhammad Z.; Michaelides, Michel; Uwaydat, Sami H.

doi:10.1016/j.ajoc.2022.101699

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…In humans, biallelic IMPG2 mutations cause retinitis pigmentosa (RP), whereas monoallelic IMPG2 mutations are linked to adult-onset vitelliform macular dystrophy (AVMD) [ 22–30 ]. Stargardt-like macular dystrophy has also been described in individuals with homozygous IMPG2 mutations [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations

Williams,

Draper,

Lang

et al. 2023

Human Molecular Genetics

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Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Towards this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with homozygous frameshift mutations (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of round white deposits surrounding the optic nerve, and disruptions of the outer retina layers and neurosensorial detachment, while the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP, and provide a toolkit and preclinical data for advancing therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations

Williams,

Draper,

Lang

et al. 2023

Human Molecular Genetics

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show abstract

“…The heterozygous IMPG2 variant (NM_016247.3:c.3423-7_3423-4del) in family 2 was originally excluded as being disease-causing for a dominantly inherited disorder due to its relatively high frequency in gnomAD. Subsequent findings have identified this variant in autosomal recessive retinitis pigmentosa patients, as well as in a patient with autosomal dominant unilateral vitelliform macular dystrophy [ 12 , 26 , 27 , 28 ]. Similarly, the heterozygous HK1 variant (NM_000188.2:c.2539G>A, p.(Glu847Lys)) in family 14 was dismissed initially due to its frequency on gnomAD and unclear family history.…”

Section: Resultsmentioning

confidence: 99%

Limited Added Diagnostic Value of Whole Genome Sequencing in Genetic Testing of Inherited Retinal Diseases in a Swiss Patient Cohort

Maggi,

Koller,

Feil

et al. 2024

IJMS

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The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES). WGS was performed for index patients in 66 families. The datasets were analyzed according to GATK’s guidelines. Additionally, DeepVariant was complemented by GATK’s workflow, and a novel structural variant pipeline was developed. Overall, a molecular diagnosis was established in 19/66 (28.8%) index patients. Pathogenic deletions and one deep-intronic variant contributed to the diagnostic yield in 4/19 and 1/19 index patients, respectively. The remaining diagnoses (14/19) were attributed to exonic variants that were missed during WES analysis due to bioinformatic limitations, newly described loci, or unclear pathogenicity. The added diagnostic value of WGS equals 5/66 (9.6%) for our cohort, which is comparable to previous studies. This figure would decrease further to 1/66 (1.5%) with a standardized and reliable copy number variant workflow during WES analysis. Given the higher costs and limited added value, the implementation of WGS as a first-tier assay for inherited eye disorders in a diagnostic laboratory remains untimely. Instead, progress in bioinformatic tools and communication between diagnostic and clinical teams have the potential to ameliorate diagnostic yields.

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Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes

Georgiou,

Robson,

Fujinami

et al. 2024

Progress in Retinal and Eye Research

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IMPG2-associated unilateral adult onset vitelliform macular dystrophy

Cited by 3 publications

References 15 publications

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations

Limited Added Diagnostic Value of Whole Genome Sequencing in Genetic Testing of Inherited Retinal Diseases in a Swiss Patient Cohort

Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes

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