Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment

Stickler syndrome is the most common cause of pediatric rhegmatogenous retinal detachments. Given the dramatic long term visual impact and difficult surgical management of these detachments, there is increasing interest in determining whether prophylactic treatment can be used to prevent retinal detachments in this population. However, severity of ocular findings in Stickler syndrome can vary by subtype. Three commonly used modalities to provide prophylactic treatment against retinal detachments in patients with Stickler syndrome include scleral buckle, laser retinopexy, and cryotherapy. While laser retinopexy is the most common approach to prophylactic treatment, treatment settings can vary by specialist. In addition, the decision to treat and manage Stickler syndrome is nuanced and requires careful consideration of the individual patient. After reviewing the literature on prophylactic treatment approaches, this chapter will also over guidelines in management of this complex patient population.

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“…Cataracts and retinal detachment have also been reported. In contrast to other subtypes, skeletal involvement appears more variable in STL6 [14].…”

Section: Genementioning

confidence: 75%

Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome

Naravane¹,

Quiram²

2023

Medical and Surgical Retina - Recent Innovation, New Perspective, and Applications

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“…Applying focused assays in concert with WGS and functional studies, as applied in this study, are becoming fruitful approaches to filling in the known limitations of clinical testing and increasing the diagnostic yield. In addition, the discovery of novel disease genes and the expansion of genotype-phenotype correlations in already described disease genes, as in our previous studies, will also increase the diagnostic yield [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies

Nash

et al. 2022

IJMS

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The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or underinvestigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs.

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“…The proband (Patient III-2, Figure 1 A) underwent a TruSight One Clinical Exome (Illumina, San Diego, CA, USA) analysis through the Molecular Genetics Department, Sydney Genome Diagnostics, at the Sydney Children’s Hospitals Network (Westmead, Australia). As in our previous studies [ 18 , 19 ], the TruSight One Clinical Exome analysis has an average depth of coverage at 160x, and it is filtered to exclude regions with a <15x read depth. The allele frequency cut-off was >0.01.…”

Section: Methodsmentioning

confidence: 99%

Human iPSC-Derived Retinal Organoids and Retinal Pigment Epithelium for Novel Intronic RPGR Variant Assessment for Therapy Suitability

Karam

Loi

et al. 2022

JPM

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The RPGR gene encodes Retinitis Pigmentosa GTPase Regulator, a known interactor with ciliary proteins, which is involved in maintaining healthy photoreceptor cells. Variants in RPGR are the main contributor to X-linked rod-cone dystrophy (RCD), and RPGR gene therapy approaches are in clinical trials. Hence, elucidation of the pathogenicity of novel RPGR variants is important for a patient therapy opportunity. Here, we describe a novel intronic RPGR variant, c.1415 − 9A>G, in a patient with RCD, which was classified as a variant of uncertain significance according to current clinical diagnostic criteria. The variant lay several base pairs intronic to the canonical splice acceptor site, raising suspicion of an RPGR RNA splicing abnormality and consequent protein dysfunction. To investigate disease causation in an appropriate disease model, induced pluripotent stem cells were generated from patient fibroblasts and differentiated to retinal pigment epithelium (iPSC-RPE) and retinal organoids (iPSC-RO). Abnormal RNA splicing of RPGR was demonstrated in patient fibroblasts, iPSC-RPE and iPSC-ROs, leading to a predicted frameshift and premature stop codon. Decreased RPGR expression was demonstrated in these cell types, with a striking loss of RPGR localization at the ciliary transitional zone, critically in the photoreceptor cilium of the patient iPSC-ROs. Mislocalisation of rhodopsin staining was present in the patient’s iPSC-RO rod photoreceptor cells, along with an abnormality of L/M opsin staining affecting cone photoreceptor cells and increased photoreceptor apoptosis. Additionally, patient iPSC-ROs displayed an increase in F-actin expression that was consistent with an abnormal actin regulation phenotype. Collectively, these studies indicate that the splicing abnormality caused by the c.1415 − 9A>G variant has an impact on RPGR function. This work has enabled the reclassification of this variant to pathogenic, allowing the consideration of patients with this variant having access to gene therapy clinical trials. In addition, we have identified biomarkers of disease suitable for the interrogation of other RPGR variants of uncertain significance.

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Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment

Cited by 10 publications

References 19 publications

Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome

Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome

Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies

Human iPSC-Derived Retinal Organoids and Retinal Pigment Epithelium for Novel Intronic RPGR Variant Assessment for Therapy Suitability

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