Identification and Analysis of Inherited Retinal Disease Genes

AbstractRetinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a gene-agnostic therapy, we screened ≈20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

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Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Genetics in Medicine ◽

10.1038/gim.2017.97 ◽

2017 ◽

Vol 20 (2) ◽

pp. 202-213 ◽

Cited By ~ 13

Author(s):

Kristof Van Schil ◽

◽

Sarah Naessens ◽

Stijn Van de Sompele ◽

Marjolein Carron ◽

...

Keyword(s):

Copy Number ◽

Retinal Disease ◽

Copy Number Variations ◽

Disease Genes ◽

Inherited Retinal Disease ◽

Genomic Landscape

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Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Genetics in Medicine ◽

10.1038/s41436-018-0305-0 ◽

2018 ◽

Vol 21 (8) ◽

pp. 1998-1998

Author(s):

Kristof Van Schil ◽

◽

Sarah Naessens ◽

Stijn Van de Sompele ◽

Marjolein Carron ◽

...

Keyword(s):

Copy Number ◽

Retinal Disease ◽

Copy Number Variations ◽

Disease Genes ◽

Inherited Retinal Disease ◽

Genomic Landscape

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AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

eLife ◽

10.7554/elife.66240 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yunlu Xue ◽

Sean K Wang ◽

Parimal Rana ◽

Emma R West ◽

Christin M Hong ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Mouse Models ◽

Retinal Disease ◽

Disease Genes ◽

Cone Photoreceptors ◽

Adeno Associated Virus ◽

Rescue Effect ◽

Inherited Retinal Disease ◽

High Acuity

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

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Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

Scientific Reports ◽

10.1038/s41598-020-80400-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ine Strubbe ◽

Caroline Van Cauwenbergh ◽

Julie De Zaeytijd ◽

Sarah De Jaegere ◽

Marieke De Bruyne ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Somatic Mosaicism ◽

Retinal Disease ◽

Hair Follicles ◽

Disease Genes ◽

Female Carrier ◽

Autofluorescence Imaging ◽

Targeted Next Generation Sequencing ◽

Whole Exome ◽

Next Generation Sequencing Ngs

AbstractWe describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.

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Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia

International Journal of Molecular Sciences ◽

10.3390/ijms22157842 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7842

Author(s):

Susanne Kohl ◽

Britta Baumann ◽

Francesca Dassie ◽

Anja K. Mayer ◽

Maria Solaki ◽

...

Keyword(s):

Segregation Analysis ◽

Molecular Genetic ◽

Retinal Disease ◽

Underlying Mechanism ◽

Recurrence Risk ◽

Molecular Genetic Analysis ◽

Recessive Mutation ◽

Chromosome 2 ◽

Inherited Retinal Disease ◽

Uniparental Isodisomy

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.

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A qualitative study among patients with an inherited retinal disease on the meaning of genomic unsolicited findings

Scientific Reports ◽

10.1038/s41598-021-95258-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marlies Saelaert ◽

Heidi Mertes ◽

Tania Moerenhout ◽

Caroline Van Cauwenbergh ◽

Bart P. Leroy ◽

...

Keyword(s):

Qualitative Study ◽

Interpretative Phenomenological Analysis ◽

Age Of Onset ◽

Genetic Diseases ◽

Retinal Disease ◽

Clinical Approach ◽

Inherited Retinal Disease ◽

Illness Experiences ◽

Meaning Structure ◽

Main Components

AbstractExome-based testing for genetic diseases can reveal unsolicited findings (UFs), i.e. predispositions for diseases that exceed the diagnostic question. Knowledge of patients’ interpretation of possible UFs and of motives for (not) wanting to know UFs is still limited. This lacking knowledge may impede effective counselling that meets patients’ needs. Therefore, this article examines the meaning of UFs from a patient perspective. A qualitative study was conducted and an interpretative phenomenological analysis was made of 14 interviews with patients with an inherited retinal disease. Patients assign a complex meaning to UFs, including three main components. The first component focuses on result-specific qualities, i.e. the characteristics of an UF (inclusive of actionability, penetrance, severity and age of onset) and the consequences of disclosure; the second component applies to a patient’s lived illness experiences and to the way these contrast with reflections on presymptomatic UFs; the third component addresses a patient’s family embedding and its effect on concerns about disease prognosis and genetic information’s family relevance. The complex meaning structure of UFs suggests the need for counselling procedures that transcend a strictly clinical approach. Counselling should be personalised and consider patients’ lived illness experiences and family context.

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